US20230248693A1 - Oral cannabinoid pharmaceutical compositions and methods of treating sleep disorders - Google Patents
Oral cannabinoid pharmaceutical compositions and methods of treating sleep disorders Download PDFInfo
- Publication number
- US20230248693A1 US20230248693A1 US18/297,973 US202318297973A US2023248693A1 US 20230248693 A1 US20230248693 A1 US 20230248693A1 US 202318297973 A US202318297973 A US 202318297973A US 2023248693 A1 US2023248693 A1 US 2023248693A1
- Authority
- US
- United States
- Prior art keywords
- api
- pulse
- cannabinoid
- sleep
- release
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000003557 cannabinoid Substances 0.000 title claims abstract description 229
- 229930003827 cannabinoid Natural products 0.000 title claims abstract description 229
- 238000000034 method Methods 0.000 title claims abstract description 72
- 208000019116 sleep disease Diseases 0.000 title claims abstract description 33
- 239000008194 pharmaceutical composition Substances 0.000 title abstract description 12
- 239000008186 active pharmaceutical agent Substances 0.000 claims description 272
- 230000007958 sleep Effects 0.000 claims description 257
- CYQFCXCEBYINGO-IAGOWNOFSA-N delta1-THC Chemical compound C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@@H]21 CYQFCXCEBYINGO-IAGOWNOFSA-N 0.000 claims description 182
- CYQFCXCEBYINGO-UHFFFAOYSA-N THC Natural products C1=C(C)CCC2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3C21 CYQFCXCEBYINGO-UHFFFAOYSA-N 0.000 claims description 173
- 229960004242 dronabinol Drugs 0.000 claims description 166
- ZTGXAWYVTLUPDT-UHFFFAOYSA-N cannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1C1C(C(C)=C)CC=C(C)C1 ZTGXAWYVTLUPDT-UHFFFAOYSA-N 0.000 claims description 139
- VBGLYOIFKLUMQG-UHFFFAOYSA-N Cannabinol Chemical compound C1=C(C)C=C2C3=C(O)C=C(CCCCC)C=C3OC(C)(C)C2=C1 VBGLYOIFKLUMQG-UHFFFAOYSA-N 0.000 claims description 136
- 229960003453 cannabinol Drugs 0.000 claims description 128
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 96
- 239000002552 dosage form Substances 0.000 claims description 92
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 55
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 55
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 55
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 55
- 235000019359 magnesium stearate Nutrition 0.000 claims description 48
- 239000000203 mixture Substances 0.000 claims description 47
- 229940065144 cannabinoids Drugs 0.000 claims description 43
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 claims description 37
- 206010022437 insomnia Diseases 0.000 claims description 37
- 230000001419 dependent effect Effects 0.000 claims description 32
- 239000012729 immediate-release (IR) formulation Substances 0.000 claims description 27
- 239000000314 lubricant Substances 0.000 claims description 27
- 230000003111 delayed effect Effects 0.000 claims description 26
- 230000036578 sleeping time Effects 0.000 claims description 26
- 238000009472 formulation Methods 0.000 claims description 23
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 22
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 22
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 22
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 22
- 229920000642 polymer Polymers 0.000 claims description 21
- 229920003145 methacrylic acid copolymer Polymers 0.000 claims description 20
- 208000020685 sleep-wake disease Diseases 0.000 claims description 20
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 19
- 230000003860 sleep quality Effects 0.000 claims description 19
- 239000011230 binding agent Substances 0.000 claims description 18
- 229940117841 methacrylic acid copolymer Drugs 0.000 claims description 18
- 230000004622 sleep time Effects 0.000 claims description 14
- 230000036385 rapid eye movement (rem) sleep Effects 0.000 claims description 12
- 239000007884 disintegrant Substances 0.000 claims description 11
- 239000012064 sodium phosphate buffer Substances 0.000 claims description 11
- XXGMIHXASFDFSM-UHFFFAOYSA-N Delta9-tetrahydrocannabinol Natural products CCCCCc1cc2OC(C)(C)C3CCC(=CC3c2c(O)c1O)C XXGMIHXASFDFSM-UHFFFAOYSA-N 0.000 claims description 10
- 206010019133 Hangover Diseases 0.000 claims description 10
- 239000007864 aqueous solution Substances 0.000 claims description 10
- 239000004014 plasticizer Substances 0.000 claims description 10
- 239000011148 porous material Substances 0.000 claims description 9
- 229940057948 magnesium stearate Drugs 0.000 claims description 6
- 230000004075 alteration Effects 0.000 claims description 4
- 238000012512 characterization method Methods 0.000 claims description 4
- 229920000623 Cellulose acetate phthalate Polymers 0.000 claims description 3
- 229940081734 cellulose acetate phthalate Drugs 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- 238000012806 monitoring device Methods 0.000 claims 4
- 239000000047 product Substances 0.000 description 176
- 241000218236 Cannabis Species 0.000 description 69
- 238000012360 testing method Methods 0.000 description 49
- 230000000694 effects Effects 0.000 description 36
- 239000003826 tablet Substances 0.000 description 29
- 238000004458 analytical method Methods 0.000 description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 25
- 230000006872 improvement Effects 0.000 description 24
- 239000003921 oil Substances 0.000 description 21
- -1 (±)-Cannabichromene Natural products 0.000 description 19
- 229940079593 drug Drugs 0.000 description 19
- 239000003814 drug Substances 0.000 description 19
- 238000000576 coating method Methods 0.000 description 17
- 229920002785 Croscarmellose sodium Polymers 0.000 description 16
- 239000011248 coating agent Substances 0.000 description 16
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 15
- 229960001681 croscarmellose sodium Drugs 0.000 description 15
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 15
- 238000003756 stirring Methods 0.000 description 15
- 206010041349 Somnolence Diseases 0.000 description 14
- 238000004090 dissolution Methods 0.000 description 14
- 238000002156 mixing Methods 0.000 description 14
- 238000011160 research Methods 0.000 description 13
- 238000011282 treatment Methods 0.000 description 13
- QHMBSVQNZZTUGM-UHFFFAOYSA-N Trans-Cannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1C1C(C(C)=C)CCC(C)=C1 QHMBSVQNZZTUGM-UHFFFAOYSA-N 0.000 description 12
- QHMBSVQNZZTUGM-ZWKOTPCHSA-N cannabidiol Chemical compound OC1=CC(CCCCC)=CC(O)=C1[C@H]1[C@H](C(C)=C)CCC(C)=C1 QHMBSVQNZZTUGM-ZWKOTPCHSA-N 0.000 description 12
- 229950011318 cannabidiol Drugs 0.000 description 11
- PCXRACLQFPRCBB-ZWKOTPCHSA-N dihydrocannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1[C@H]1[C@H](C(C)C)CCC(C)=C1 PCXRACLQFPRCBB-ZWKOTPCHSA-N 0.000 description 11
- 239000000758 substrate Substances 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 230000008901 benefit Effects 0.000 description 10
- 230000002496 gastric effect Effects 0.000 description 10
- 239000006186 oral dosage form Substances 0.000 description 10
- 239000000843 powder Substances 0.000 description 10
- 230000002618 waking effect Effects 0.000 description 10
- 241000651994 Curio Species 0.000 description 9
- 206010062519 Poor quality sleep Diseases 0.000 description 9
- 238000000338 in vitro Methods 0.000 description 9
- 238000012935 Averaging Methods 0.000 description 8
- 229920001577 copolymer Polymers 0.000 description 8
- 238000012423 maintenance Methods 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 230000004461 rapid eye movement Effects 0.000 description 8
- 230000003247 decreasing effect Effects 0.000 description 7
- 210000001035 gastrointestinal tract Anatomy 0.000 description 7
- 238000002483 medication Methods 0.000 description 7
- 239000008203 oral pharmaceutical composition Substances 0.000 description 7
- 230000000391 smoking effect Effects 0.000 description 7
- 208000024891 symptom Diseases 0.000 description 7
- 208000025721 COVID-19 Diseases 0.000 description 6
- 208000032140 Sleepiness Diseases 0.000 description 6
- 239000000872 buffer Substances 0.000 description 6
- IGHTZQUIFGUJTG-UHFFFAOYSA-N cannabicyclol Chemical compound O1C2=CC(CCCCC)=CC(O)=C2C2C(C)(C)C3C2C1(C)CC3 IGHTZQUIFGUJTG-UHFFFAOYSA-N 0.000 description 6
- 230000008859 change Effects 0.000 description 6
- 238000013461 design Methods 0.000 description 6
- 230000036541 health Effects 0.000 description 6
- 239000002609 medium Substances 0.000 description 6
- 229920001223 polyethylene glycol Polymers 0.000 description 6
- 230000037321 sleepiness Effects 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- IXJXRDCCQRZSDV-GCKMJXCFSA-N (6ar,9r,10as)-6,6,9-trimethyl-3-pentyl-6a,7,8,9,10,10a-hexahydro-6h-1,9-epoxybenzo[c]chromene Chemical compound C1C[C@@H](C(O2)(C)C)[C@@H]3C[C@]1(C)OC1=C3C2=CC(CCCCC)=C1 IXJXRDCCQRZSDV-GCKMJXCFSA-N 0.000 description 5
- 241000282414 Homo sapiens Species 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 238000005259 measurement Methods 0.000 description 5
- 230000008447 perception Effects 0.000 description 5
- 229920000058 polyacrylate Polymers 0.000 description 5
- 230000004044 response Effects 0.000 description 5
- 235000000346 sugar Nutrition 0.000 description 5
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 4
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 4
- AAXZFUQLLRMVOG-UHFFFAOYSA-N 2-methyl-2-(4-methylpent-3-enyl)-7-propylchromen-5-ol Chemical compound C1=CC(C)(CCC=C(C)C)OC2=CC(CCC)=CC(O)=C21 AAXZFUQLLRMVOG-UHFFFAOYSA-N 0.000 description 4
- WVOLTBSCXRRQFR-SJORKVTESA-N Cannabidiolic acid Natural products OC1=C(C(O)=O)C(CCCCC)=CC(O)=C1[C@@H]1[C@@H](C(C)=C)CCC(C)=C1 WVOLTBSCXRRQFR-SJORKVTESA-N 0.000 description 4
- 229920003134 Eudragit® polymer Polymers 0.000 description 4
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 4
- 239000001045 blue dye Substances 0.000 description 4
- WVOLTBSCXRRQFR-DLBZAZTESA-N cannabidiolic acid Chemical compound OC1=C(C(O)=O)C(CCCCC)=CC(O)=C1[C@H]1[C@H](C(C)=C)CCC(C)=C1 WVOLTBSCXRRQFR-DLBZAZTESA-N 0.000 description 4
- 238000009506 drug dissolution testing Methods 0.000 description 4
- 238000013265 extended release Methods 0.000 description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 4
- 230000004617 sleep duration Effects 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- RBEAVAMWZAJWOI-MTOHEIAKSA-N (5as,6s,9r,9ar)-6-methyl-3-pentyl-9-prop-1-en-2-yl-7,8,9,9a-tetrahydro-5ah-dibenzofuran-1,6-diol Chemical compound C1=2C(O)=CC(CCCCC)=CC=2O[C@H]2[C@@H]1[C@H](C(C)=C)CC[C@]2(C)O RBEAVAMWZAJWOI-MTOHEIAKSA-N 0.000 description 3
- WIDIPARNVYRVNW-CHWSQXEVSA-N (6ar,10ar)-3,6,6,9-tetramethyl-6a,7,8,10a-tetrahydrobenzo[c]chromen-1-ol Chemical compound CC1=CC(O)=C2[C@@H]3C=C(C)CC[C@H]3C(C)(C)OC2=C1 WIDIPARNVYRVNW-CHWSQXEVSA-N 0.000 description 3
- ZROLHBHDLIHEMS-HUUCEWRRSA-N (6ar,10ar)-6,6,9-trimethyl-3-propyl-6a,7,8,10a-tetrahydrobenzo[c]chromen-1-ol Chemical compound C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCC)=CC(O)=C3[C@@H]21 ZROLHBHDLIHEMS-HUUCEWRRSA-N 0.000 description 3
- SERLAGPUMNYUCK-DCUALPFSSA-N 1-O-alpha-D-glucopyranosyl-D-mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O SERLAGPUMNYUCK-DCUALPFSSA-N 0.000 description 3
- YJYIDZLGVYOPGU-XNTDXEJSSA-N 2-[(2e)-3,7-dimethylocta-2,6-dienyl]-5-propylbenzene-1,3-diol Chemical compound CCCC1=CC(O)=C(C\C=C(/C)CCC=C(C)C)C(O)=C1 YJYIDZLGVYOPGU-XNTDXEJSSA-N 0.000 description 3
- UVOLYTDXHDXWJU-UHFFFAOYSA-N Cannabichromene Chemical compound C1=CC(C)(CCC=C(C)C)OC2=CC(CCCCC)=CC(O)=C21 UVOLYTDXHDXWJU-UHFFFAOYSA-N 0.000 description 3
- UVOLYTDXHDXWJU-NRFANRHFSA-N Cannabichromene Natural products C1=C[C@](C)(CCC=C(C)C)OC2=CC(CCCCC)=CC(O)=C21 UVOLYTDXHDXWJU-NRFANRHFSA-N 0.000 description 3
- 244000025254 Cannabis sativa Species 0.000 description 3
- 235000012766 Cannabis sativa ssp. sativa var. sativa Nutrition 0.000 description 3
- 235000012765 Cannabis sativa ssp. sativa var. spontanea Nutrition 0.000 description 3
- ZLHQMHUXJUPEHK-UHFFFAOYSA-N Cannabivarin Natural products CCCc1cc(O)c2c(OC(C)(C)c3ccccc23)c1 ZLHQMHUXJUPEHK-UHFFFAOYSA-N 0.000 description 3
- 229920001661 Chitosan Polymers 0.000 description 3
- UCONUSSAWGCZMV-HZPDHXFCSA-N Delta(9)-tetrahydrocannabinolic acid Chemical compound C([C@H]1C(C)(C)O2)CC(C)=C[C@H]1C1=C2C=C(CCCCC)C(C(O)=O)=C1O UCONUSSAWGCZMV-HZPDHXFCSA-N 0.000 description 3
- ORKZJYDOERTGKY-UHFFFAOYSA-N Dihydrocannabichromen Natural products C1CC(C)(CCC=C(C)C)OC2=CC(CCCCC)=CC(O)=C21 ORKZJYDOERTGKY-UHFFFAOYSA-N 0.000 description 3
- 229920003157 Eudragit® RL 30 D Polymers 0.000 description 3
- 229920003161 Eudragit® RS 30 D Polymers 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 3
- 206010022035 Initial insomnia Diseases 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- 101100268917 Oryctolagus cuniculus ACOX2 gene Proteins 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- UCONUSSAWGCZMV-UHFFFAOYSA-N Tetrahydro-cannabinol-carbonsaeure Natural products O1C(C)(C)C2CCC(C)=CC2C2=C1C=C(CCCCC)C(C(O)=O)=C2O UCONUSSAWGCZMV-UHFFFAOYSA-N 0.000 description 3
- 238000013459 approach Methods 0.000 description 3
- QXACEHWTBCFNSA-SFQUDFHCSA-N cannabigerol Chemical compound CCCCCC1=CC(O)=C(C\C=C(/C)CCC=C(C)C)C(O)=C1 QXACEHWTBCFNSA-SFQUDFHCSA-N 0.000 description 3
- QXACEHWTBCFNSA-UHFFFAOYSA-N cannabigerol Natural products CCCCCC1=CC(O)=C(CC=C(C)CCC=C(C)C)C(O)=C1 QXACEHWTBCFNSA-UHFFFAOYSA-N 0.000 description 3
- YJYIDZLGVYOPGU-UHFFFAOYSA-N cannabigeroldivarin Natural products CCCC1=CC(O)=C(CC=C(C)CCC=C(C)C)C(O)=C1 YJYIDZLGVYOPGU-UHFFFAOYSA-N 0.000 description 3
- SEEZIOZEUUMJME-VBKFSLOCSA-N cannabinerolic acid Chemical compound CCCCCC1=CC(O)=C(C\C=C(\C)CCC=C(C)C)C(O)=C1C(O)=O SEEZIOZEUUMJME-VBKFSLOCSA-N 0.000 description 3
- SEEZIOZEUUMJME-UHFFFAOYSA-N cannabinerolic acid Natural products CCCCCC1=CC(O)=C(CC=C(C)CCC=C(C)C)C(O)=C1C(O)=O SEEZIOZEUUMJME-UHFFFAOYSA-N 0.000 description 3
- SVTKBAIRFMXQQF-UHFFFAOYSA-N cannabivarin Chemical compound C1=C(C)C=C2C3=C(O)C=C(CCC)C=C3OC(C)(C)C2=C1 SVTKBAIRFMXQQF-UHFFFAOYSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000013480 data collection Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 3
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 239000000905 isomalt Substances 0.000 description 3
- 235000010439 isomalt Nutrition 0.000 description 3
- HPIGCVXMBGOWTF-UHFFFAOYSA-N isomaltol Natural products CC(=O)C=1OC=CC=1O HPIGCVXMBGOWTF-UHFFFAOYSA-N 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 230000033001 locomotion Effects 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000002207 metabolite Substances 0.000 description 3
- 230000036407 pain Effects 0.000 description 3
- 230000035699 permeability Effects 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 3
- 230000000541 pulsatile effect Effects 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 238000012552 review Methods 0.000 description 3
- 238000005070 sampling Methods 0.000 description 3
- 230000008667 sleep stage Effects 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 238000010200 validation analysis Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 2
- KXKOBIRSQLNUPS-UHFFFAOYSA-N 1-hydroxy-6,6,9-trimethyl-3-pentylbenzo[c]chromene-2-carboxylic acid Chemical compound O1C(C)(C)C2=CC=C(C)C=C2C2=C1C=C(CCCCC)C(C(O)=O)=C2O KXKOBIRSQLNUPS-UHFFFAOYSA-N 0.000 description 2
- TWKHUZXSTKISQC-UHFFFAOYSA-N 2-(5-methyl-2-prop-1-en-2-ylphenyl)-5-pentylbenzene-1,3-diol Chemical compound OC1=CC(CCCCC)=CC(O)=C1C1=CC(C)=CC=C1C(C)=C TWKHUZXSTKISQC-UHFFFAOYSA-N 0.000 description 2
- NHZMSIOYBVIOAF-UHFFFAOYSA-N 5-hydroxy-2,2-dimethyl-3-(3-oxobutyl)-7-pentyl-3h-chromen-4-one Chemical compound O=C1C(CCC(C)=O)C(C)(C)OC2=CC(CCCCC)=CC(O)=C21 NHZMSIOYBVIOAF-UHFFFAOYSA-N 0.000 description 2
- NAGBBYZBIQVPIQ-UHFFFAOYSA-N 6-methyl-3-pentyl-9-prop-1-en-2-yldibenzofuran-1-ol Chemical compound C1=CC(C(C)=C)=C2C3=C(O)C=C(CCCCC)C=C3OC2=C1C NAGBBYZBIQVPIQ-UHFFFAOYSA-N 0.000 description 2
- VNGQMWZHHNCMLQ-UHFFFAOYSA-N 6-methyl-3-pentyl-9-propan-2-yldibenzofuran-1-ol Chemical compound C1=CC(C(C)C)=C2C3=C(O)C=C(CCCCC)C=C3OC2=C1C VNGQMWZHHNCMLQ-UHFFFAOYSA-N 0.000 description 2
- 229920000178 Acrylic resin Polymers 0.000 description 2
- 239000004925 Acrylic resin Substances 0.000 description 2
- 208000019901 Anxiety disease Diseases 0.000 description 2
- REOZWEGFPHTFEI-JKSUJKDBSA-N Cannabidivarin Chemical compound OC1=CC(CCC)=CC(O)=C1[C@H]1[C@H](C(C)=C)CCC(C)=C1 REOZWEGFPHTFEI-JKSUJKDBSA-N 0.000 description 2
- KASVLYINZPAMNS-UHFFFAOYSA-N Cannabigerol monomethylether Natural products CCCCCC1=CC(O)=C(CC=C(C)CCC=C(C)C)C(OC)=C1 KASVLYINZPAMNS-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- ZROLHBHDLIHEMS-UHFFFAOYSA-N Delta9 tetrahydrocannabivarin Natural products C1=C(C)CCC2C(C)(C)OC3=CC(CCC)=CC(O)=C3C21 ZROLHBHDLIHEMS-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 239000001856 Ethyl cellulose Substances 0.000 description 2
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 2
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 2
- 208000011688 Generalised anxiety disease Diseases 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 2
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 241001597135 Neodidymelliopsis cannabis Species 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 208000010340 Sleep Deprivation Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229920002125 Sokalan® Polymers 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 230000036506 anxiety Effects 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 230000036983 biotransformation Effects 0.000 description 2
- REOZWEGFPHTFEI-UHFFFAOYSA-N cannabidivarine Natural products OC1=CC(CCC)=CC(O)=C1C1C(C(C)=C)CCC(C)=C1 REOZWEGFPHTFEI-UHFFFAOYSA-N 0.000 description 2
- SEEZIOZEUUMJME-FOWTUZBSSA-N cannabigerolic acid Chemical compound CCCCCC1=CC(O)=C(C\C=C(/C)CCC=C(C)C)C(O)=C1C(O)=O SEEZIOZEUUMJME-FOWTUZBSSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000000332 continued effect Effects 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 230000001186 cumulative effect Effects 0.000 description 2
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 2
- 238000007405 data analysis Methods 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 231100000517 death Toxicity 0.000 description 2
- 230000002939 deleterious effect Effects 0.000 description 2
- 239000002274 desiccant Substances 0.000 description 2
- FLKPEMZONWLCSK-UHFFFAOYSA-N diethyl phthalate Chemical compound CCOC(=O)C1=CC=CC=C1C(=O)OCC FLKPEMZONWLCSK-UHFFFAOYSA-N 0.000 description 2
- 230000001079 digestive effect Effects 0.000 description 2
- 239000012738 dissolution medium Substances 0.000 description 2
- 238000011978 dissolution method Methods 0.000 description 2
- 238000007922 dissolution test Methods 0.000 description 2
- 210000001198 duodenum Anatomy 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 229920001249 ethyl cellulose Polymers 0.000 description 2
- 235000019325 ethyl cellulose Nutrition 0.000 description 2
- 230000037406 food intake Effects 0.000 description 2
- 229960002737 fructose Drugs 0.000 description 2
- 208000029364 generalized anxiety disease Diseases 0.000 description 2
- 229940075507 glyceryl monostearate Drugs 0.000 description 2
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 239000002050 international nonproprietary name Substances 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 238000002372 labelling Methods 0.000 description 2
- 239000004922 lacquer Substances 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 230000036961 partial effect Effects 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 239000000902 placebo Substances 0.000 description 2
- 229940068196 placebo Drugs 0.000 description 2
- 239000001253 polyvinylpolypyrrolidone Substances 0.000 description 2
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 2
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 125000001453 quaternary ammonium group Chemical group 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 229940100486 rice starch Drugs 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 229920003109 sodium starch glycolate Polymers 0.000 description 2
- 239000008109 sodium starch glycolate Substances 0.000 description 2
- 229940079832 sodium starch glycolate Drugs 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000001593 sorbitan monooleate Substances 0.000 description 2
- 235000011069 sorbitan monooleate Nutrition 0.000 description 2
- 229940035049 sorbitan monooleate Drugs 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 230000002459 sustained effect Effects 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 230000009897 systematic effect Effects 0.000 description 2
- 230000002123 temporal effect Effects 0.000 description 2
- 210000002700 urine Anatomy 0.000 description 2
- 230000002747 voluntary effect Effects 0.000 description 2
- 239000002023 wood Substances 0.000 description 2
- BWFHYGJGKLAXKO-VXGBXAGGSA-N (6ar,10ar)-1-hydroxy-3,6,6,9-tetramethyl-6a,7,8,10a-tetrahydrobenzo[c]chromene-2-carboxylic acid Chemical compound CC1=C(C(O)=O)C(O)=C2[C@@H]3C=C(C)CC[C@H]3C(C)(C)OC2=C1 BWFHYGJGKLAXKO-VXGBXAGGSA-N 0.000 description 1
- FUIFGAFTCQIBQJ-VXGBXAGGSA-N (6ar,10ar)-1-hydroxy-3,6,6,9-tetramethyl-6a,7,8,10a-tetrahydrobenzo[c]chromene-4-carboxylic acid Chemical compound OC1=CC(C)=C(C(O)=O)C2=C1[C@@H]1C=C(C)CC[C@H]1C(C)(C)O2 FUIFGAFTCQIBQJ-VXGBXAGGSA-N 0.000 description 1
- IQSYWEWTWDEVNO-ZIAGYGMSSA-N (6ar,10ar)-1-hydroxy-6,6,9-trimethyl-3-propyl-6a,7,8,10a-tetrahydrobenzo[c]chromene-2-carboxylic acid Chemical compound C([C@H]1C(C)(C)O2)CC(C)=C[C@H]1C1=C2C=C(CCC)C(C(O)=O)=C1O IQSYWEWTWDEVNO-ZIAGYGMSSA-N 0.000 description 1
- TZFPIQSSTVIJTQ-HUUCEWRRSA-N (6ar,10ar)-3-butyl-1-hydroxy-6,6,9-trimethyl-6a,7,8,10a-tetrahydrobenzo[c]chromene-2-carboxylic acid Chemical compound C([C@H]1C(C)(C)O2)CC(C)=C[C@H]1C1=C2C=C(CCCC)C(C(O)=O)=C1O TZFPIQSSTVIJTQ-HUUCEWRRSA-N 0.000 description 1
- TZGCTXUTNDNTTE-DYZHCLJRSA-N (6ar,9s,10s,10ar)-6,6,9-trimethyl-3-pentyl-7,8,10,10a-tetrahydro-6ah-benzo[c]chromene-1,9,10-triol Chemical compound O[C@@H]1[C@@](C)(O)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@@H]21 TZGCTXUTNDNTTE-DYZHCLJRSA-N 0.000 description 1
- YEDIZIGYIMTZKP-UHFFFAOYSA-N 1-methoxy-6,6,9-trimethyl-3-pentylbenzo[c]chromene Chemical compound C1=C(C)C=C2C3=C(OC)C=C(CCCCC)C=C3OC(C)(C)C2=C1 YEDIZIGYIMTZKP-UHFFFAOYSA-N 0.000 description 1
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
- YCBKSSAWEUDACY-IAGOWNOFSA-N 11-hydroxy-Delta(9)-tetrahydrocannabinol Chemical compound C1=C(CO)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@@H]21 YCBKSSAWEUDACY-IAGOWNOFSA-N 0.000 description 1
- 239000000263 2,3-dihydroxypropyl (Z)-octadec-9-enoate Substances 0.000 description 1
- CZXWOKHVLNYAHI-LSDHHAIUSA-N 2,4-dihydroxy-3-[(1r,6r)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]-6-propylbenzoic acid Chemical compound OC1=C(C(O)=O)C(CCC)=CC(O)=C1[C@H]1[C@H](C(C)=C)CCC(C)=C1 CZXWOKHVLNYAHI-LSDHHAIUSA-N 0.000 description 1
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- COURSARJQZMTEZ-UHFFFAOYSA-N 2-(5-methyl-2-prop-1-en-2-ylphenyl)-5-propylbenzene-1,3-diol Chemical compound OC1=CC(CCC)=CC(O)=C1C1=CC(C)=CC=C1C(C)=C COURSARJQZMTEZ-UHFFFAOYSA-N 0.000 description 1
- VKNASXZDGZNEDA-UHFFFAOYSA-N 2-cyanoethyl 2-methylprop-2-enoate Chemical compound CC(=C)C(=O)OCCC#N VKNASXZDGZNEDA-UHFFFAOYSA-N 0.000 description 1
- SFPNZPQIIAJXGL-UHFFFAOYSA-N 2-ethoxyethyl 2-methylprop-2-enoate Chemical class CCOCCOC(=O)C(C)=C SFPNZPQIIAJXGL-UHFFFAOYSA-N 0.000 description 1
- XWIWWMIPMYDFOV-UHFFFAOYSA-N 3,6,6,9-tetramethylbenzo[c]chromen-1-ol Chemical compound C1=C(C)C=C2OC(C)(C)C3=CC=C(C)C=C3C2=C1O XWIWWMIPMYDFOV-UHFFFAOYSA-N 0.000 description 1
- FAVCTJGKHFHFHJ-GXDHUFHOSA-N 3-[(2e)-3,7-dimethylocta-2,6-dienyl]-2,4-dihydroxy-6-propylbenzoic acid Chemical compound CCCC1=CC(O)=C(C\C=C(/C)CCC=C(C)C)C(O)=C1C(O)=O FAVCTJGKHFHFHJ-GXDHUFHOSA-N 0.000 description 1
- GGVVJZIANMUEJO-UHFFFAOYSA-N 3-butyl-6,6,9-trimethylbenzo[c]chromen-1-ol Chemical compound C1=C(C)C=C2C3=C(O)C=C(CCCC)C=C3OC(C)(C)C2=C1 GGVVJZIANMUEJO-UHFFFAOYSA-N 0.000 description 1
- QUYCDNSZSMEFBQ-UHFFFAOYSA-N 3-ethyl-6,6,9-trimethylbenzo[c]chromen-1-ol Chemical compound C1=C(C)C=C2C3=C(O)C=C(CC)C=C3OC(C)(C)C2=C1 QUYCDNSZSMEFBQ-UHFFFAOYSA-N 0.000 description 1
- RZRNAYUHWVFMIP-GDCKJWNLSA-N 3-oleoyl-sn-glycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](O)CO RZRNAYUHWVFMIP-GDCKJWNLSA-N 0.000 description 1
- WBRXESQKGXYDOL-DLBZAZTESA-N 5-butyl-2-[(1r,6r)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]benzene-1,3-diol Chemical compound OC1=CC(CCCC)=CC(O)=C1[C@H]1[C@H](C(C)=C)CCC(C)=C1 WBRXESQKGXYDOL-DLBZAZTESA-N 0.000 description 1
- GKVOVXWEBSQJPA-UONOGXRCSA-N 5-methyl-2-[(1r,6r)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]benzene-1,3-diol Chemical compound CC(=C)[C@@H]1CCC(C)=C[C@H]1C1=C(O)C=C(C)C=C1O GKVOVXWEBSQJPA-UONOGXRCSA-N 0.000 description 1
- INKUWBOHCFHXTJ-OFLPRAFFSA-N 8-β-hydroxy-δ-9-thc Chemical compound C1=C(C)[C@H](O)CC2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3C21 INKUWBOHCFHXTJ-OFLPRAFFSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 229920002126 Acrylic acid copolymer Polymers 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 208000020925 Bipolar disease Diseases 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 102000018208 Cannabinoid Receptor Human genes 0.000 description 1
- 108050007331 Cannabinoid receptor Proteins 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- PYGXAGIECVVIOZ-UHFFFAOYSA-N Dibutyl decanedioate Chemical compound CCCCOC(=O)CCCCCCCCC(=O)OCCCC PYGXAGIECVVIOZ-UHFFFAOYSA-N 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- 208000007590 Disorders of Excessive Somnolence Diseases 0.000 description 1
- CYQFCXCEBYINGO-DLBZAZTESA-N Dronabinol Natural products C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@H]21 CYQFCXCEBYINGO-DLBZAZTESA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 description 1
- 229920003139 Eudragit® L 100 Polymers 0.000 description 1
- 229920003136 Eudragit® L polymer Polymers 0.000 description 1
- 229920003151 Eudragit® RL polymer Polymers 0.000 description 1
- 229920003152 Eudragit® RS polymer Polymers 0.000 description 1
- 229920003141 Eudragit® S 100 Polymers 0.000 description 1
- 241001539473 Euphoria Species 0.000 description 1
- 206010015535 Euphoric mood Diseases 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 239000005913 Maltodextrin Substances 0.000 description 1
- 229920002774 Maltodextrin Polymers 0.000 description 1
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 150000001200 N-acyl ethanolamides Chemical class 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 229920002845 Poly(methacrylic acid) Polymers 0.000 description 1
- 208000005793 Restless legs syndrome Diseases 0.000 description 1
- 206010039897 Sedation Diseases 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001252 acrylic acid derivatives Chemical class 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 235000013334 alcoholic beverage Nutrition 0.000 description 1
- 229920003144 amino alkyl methacrylate copolymer Polymers 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium group Chemical group [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- LGEQQWMQCRIYKG-DOFZRALJSA-N anandamide Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(=O)NCCO LGEQQWMQCRIYKG-DOFZRALJSA-N 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 230000001773 anti-convulsant effect Effects 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 229940111121 antirheumatic drug quinolines Drugs 0.000 description 1
- LGEQQWMQCRIYKG-UHFFFAOYSA-N arachidonic acid ethanolamide Natural products CCCCCC=CCC=CCC=CCC=CCCCC(=O)NCCO LGEQQWMQCRIYKG-UHFFFAOYSA-N 0.000 description 1
- 125000004421 aryl sulphonamide group Chemical group 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 229930192457 cannabichromanone Natural products 0.000 description 1
- CSSYBWPIBDITMG-UHFFFAOYSA-N cannabicoumaronone Chemical compound O1C(C)(C)C(CCC(C)=O)C2=COC3=CC(CCCCC)=CC1=C32 CSSYBWPIBDITMG-UHFFFAOYSA-N 0.000 description 1
- 230000003375 cannabimimetic effect Effects 0.000 description 1
- ZLYNXDIDWUWASO-UHFFFAOYSA-N cannabitriol Natural products CC1(C)OC2=CC(CCCCC)=CC(O)=C2C2=C1CCC(C)(O)C2O ZLYNXDIDWUWASO-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 229940099112 cornstarch Drugs 0.000 description 1
- 229960005168 croscarmellose Drugs 0.000 description 1
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002716 delivery method Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 229940031954 dibutyl sebacate Drugs 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940126534 drug product Drugs 0.000 description 1
- 150000002066 eicosanoids Chemical class 0.000 description 1
- 238000004520 electroporation Methods 0.000 description 1
- 230000002996 emotional effect Effects 0.000 description 1
- 239000002621 endocannabinoid Substances 0.000 description 1
- 239000006274 endogenous ligand Substances 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 210000003608 fece Anatomy 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000010408 film Substances 0.000 description 1
- 230000000762 glandular Effects 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229930182480 glucuronide Natural products 0.000 description 1
- 150000008134 glucuronides Chemical class 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 229920000591 gum Polymers 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 239000012943 hotmelt Substances 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 229920000639 hydroxypropylmethylcellulose acetate succinate Polymers 0.000 description 1
- 230000000147 hypnotic effect Effects 0.000 description 1
- 238000007654 immersion Methods 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 229940035034 maltodextrin Drugs 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 229940057917 medium chain triglycerides Drugs 0.000 description 1
- 125000005397 methacrylic acid ester group Chemical group 0.000 description 1
- 125000005395 methacrylic acid group Chemical group 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- RIEABXYBQSLTFR-UHFFFAOYSA-N monobutyrin Chemical compound CCCC(=O)OCC(O)CO RIEABXYBQSLTFR-UHFFFAOYSA-N 0.000 description 1
- RZRNAYUHWVFMIP-UHFFFAOYSA-N monoelaidin Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC(O)CO RZRNAYUHWVFMIP-UHFFFAOYSA-N 0.000 description 1
- 230000001459 mortal effect Effects 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- 201000003631 narcolepsy Diseases 0.000 description 1
- 230000000422 nocturnal effect Effects 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 239000000820 nonprescription drug Substances 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000006191 orally-disintegrating tablet Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940023488 pill Drugs 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 238000007747 plating Methods 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920003229 poly(methyl methacrylate) Polymers 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 229920000193 polymethacrylate Polymers 0.000 description 1
- 239000004926 polymethyl methacrylate Substances 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 229940116317 potato starch Drugs 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 239000000955 prescription drug Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 229940001470 psychoactive drug Drugs 0.000 description 1
- 239000004089 psychotropic agent Substances 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 239000007889 pulsatile dosage form Substances 0.000 description 1
- 150000003248 quinolines Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 201000002859 sleep apnea Diseases 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 229940083542 sodium Drugs 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- IUEMQUIQAPPJDL-UHFFFAOYSA-M sodium;2,3-dihydroxypropanoate Chemical compound [Na+].OCC(O)C([O-])=O IUEMQUIQAPPJDL-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000006190 sub-lingual tablet Substances 0.000 description 1
- 229940098466 sublingual tablet Drugs 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000012353 t test Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- QHCQSGYWGBDSIY-HZPDHXFCSA-N tetrahydrocannabinol-c4 Chemical compound C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCC)=CC(O)=C3[C@@H]21 QHCQSGYWGBDSIY-HZPDHXFCSA-N 0.000 description 1
- 210000000115 thoracic cavity Anatomy 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 238000012876 topography Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 230000036642 wellbeing Effects 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
- A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
Definitions
- the present disclosure relates to oral cannabinoid pharmaceutical compositions and methods of treating sleep disorders using the oral cannabinoid pharmaceutical compositions.
- Insufficient sleep is associated with a plethora of adverse health conditions including diabetes, hypertension, heart disease, stroke, depression, obesity, impaired immune function and increased risk of death (Watson et al., Sleep. 2015 Aug. 1; 38(8):1161-83).
- Existing sleep aids can often be ineffective or only marginally effective, and some may have a profound deleterious impact on quality of sleep, in particular on REM sleep and deep sleep components of the sleep experience.
- development of improved sleep medications is challenging.
- the present disclosure relates provides an oral pulse-release dosage form, comprising a total daily dose of a first cannabinoid active pharmaceutical ingredient (API 1 ) and a total daily dose of a second cannabinoid API (API 2 ).
- the oral pulse-release dosage form comprises a first pulse-release component (C 1 ) comprising a first portion (P 1 ) of the first cannabinoid API (API 1 P 1 ) and a first portion (P 1 ) of the second cannabinoid API (API 2 P 1 ).
- the oral pulse-release dosage form also comprises at least a second pulse-release component (C 2 ) comprising a second portion (P 2 ) of the first cannabinoid API (API 1 P 2 ) and a second portion (P 2 ) of the second cannabinoid API (API 2 P 2 ).
- the total daily dose of each of the API 1 and the API 2 is divided between the first portion (P 1 ) in the first pulse-release component (C 1 ) and at least the second portion (P 2 ) in the at least second pulse-release component (C 2 ).
- the pulse-release dosage form When the pulse-release dosage form is placed in an aqueous solution of 0.1N HCl pH 1.1 for 2 hours followed by 8 hours in sodium phosphate buffer at pH 6.8, at 37° C. ⁇ 0.5° C., the pulse-release dosage form provides release of the API 1 P 2 and the API 2 P 2 beginning from 2 to 6 hours after release of the API 1 P 1 and the API 2 P 1 begins.
- the oral pulse-release dosage form may include the following details, which can be combined with one another in any combinations unless clearly mutually exclusive:
- the pulse-release dosage form may provide a second time of peak release rate (PRR 2 ) of each of the API 1 (PRR 2 API 1 ) and the API 2 (PRR 2 API 2 ) from about 2 to 6 hours after a first time of PRR (PRR 1 ).
- the PRR 1 may be after 1-2 hours.
- the first cannabinoid API 1 may be delta-9-tetrahydrocannabinol (THC) and the second cannabinoid API 2 may be cannabinol (CBN).
- THC delta-9-tetrahydrocannabinol
- CBN cannabinol
- the total daily dose of the THC may be from 1 mg to 40 mg and the total daily dose of the CBN may be from 2.5 mg to 100 mg.
- the first cannabinoid API 1 may be THC and the second cannabinoid API 2 may be CBN.
- the total daily dose of the THC may be selected from: at least 1 mg, at least 2 mg, at least 3 mg, at least 4 mg, at least 5 mg, at least 6 mg, at least 8 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, and at least 35 mg
- the total daily dose of the CBN may be selected from: at least 2.5 mg, at least 3 mg, at least 4 mg, at least 5 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, and at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, and at least 95 mg.
- the first pulse-release component (C 1 ) may be an immediate release (IR) formulation of the first cannabinoid API 1 and the second cannabinoid API 2 , comprising: the first portion (P 1 ) of the first cannabinoid API (API 1 P 1 ) and a first portion (P 1 ) of the second cannabinoid API (API 2 P 1 ), and one or more binders, one or more disintegrants, one or more lubricants, one or more flow aids, or any combinations thereof.
- IR immediate release
- the second pulse-release component (C 2 ) may be a delayed release (DR) formulation of the first cannabinoid API 1 and the second cannabinoid API 2 , comprising: the second portion (P 2 ) of the first cannabinoid API (API 1 P 2 ) and a second portion (P 2 ) of the second cannabinoid API (API 2 P 2 ), and one or more binders, one or more lubricants, one or more flow aids, or any combinations thereof.
- DR delayed release
- the second pulse-release component may be coated with a delayed-release layer comprising one or more pH-dependent and/or non-pH-dependent polymers, and optionally one or more plasticizers, one or more pore formers, or one or lubricants, or any combinations thereof.
- the first portion (P 1 ) may be independently selected from 25% to 75% of the total daily dose
- the second portion (P 2 ) may be independently selected from 25% to 75% of the total daily dose.
- the binders may comprise from 1 to 60% (w/w)
- the disintegrants may comprise from 0.05 to 15% (w/w)
- the lubricants may comprise from 0.5 to 5% (w/w)
- the flow aids may comprise from 0.05 to 0.5% (w/w)
- the pH-dependent and/or non-pH-dependent polymers may comprise from 0.5 to 35% (w/w).
- the first pulse-release component (C 1 ) may comprise from 0.5 mg to 30 mg of the first cannabinoid active pharmaceutical ingredient (API 1 ), wherein the API 1 is THC, and from 1.25 mg to 75 mg of the second cannabinoid active pharmaceutical ingredient (API 1 ), wherein the API 1 is CBN.
- the first pulse-release component (C 1 ) may comprise microcrystalline cellulose, hydroxypropylmethylcellulose, and magnesium stearate.
- the second pulse-release component (C 2 ) may comprise from 0.5 mg to 30 mg of the first cannabinoid active pharmaceutical ingredient (API 1 ), wherein the API 1 is THC, and from 1.25 mg to 75 mg of the second cannabinoid active pharmaceutical ingredient (API 1 ), wherein the API 1 is CBN.
- the second pulse-release component (C 2 ) may comprise microcrystalline cellulose, methacrylic acid copolymer, magnesium stearate, and colloidal silicone dioxide.
- the present disclosure relates provides an oral pulse-release dosage form, comprising a total daily dose of a first cannabinoid active pharmaceutical ingredient (API 1 ) and a total daily dose of a second cannabinoid API (API 2 ).
- API 1 cannabinoid active pharmaceutical ingredient
- API 2 cannabinoid API
- the pulse-release dosage form comprises a first pulse-release component (C 1 ) comprising a first portion (P 1 ) of the first cannabinoid API (API 1 P 1 ) and a first portion (P 1 ) of the second cannabinoid API (API 2 P 1 ), a second pulse-release component (C 2 ) comprising a second portion (P 2 ) of the first cannabinoid API (API 1 P 2 ) and a second portion (P 2 ) of the second cannabinoid API (API 2 P 2 ), and at least a third pulse-release component (C 3 ) comprising a third portion (P 3 ) of the first cannabinoid API (API 1 P 3 ) and a third portion (P 3 ) of the second cannabinoid API (API 2 P 2 ).
- the total daily dose of each of the API 1 and the API 2 may be divided between the first portion (P 1 ) in the first pulse-release component (C 1 ), the second portion (P 2 ) in the second pulse-release component (C 2 ), and at least the third portion (P 3 ) in the at least third pulse-release component (C 3 ).
- the pulse-release dosage form When the pulse-release dosage form is placed in an aqueous solution of 0.1N HCl pH 1.1 for 2 hours followed by 8 hours in sodium phosphate buffer at pH 6.8, at 37° C. ⁇ 0.5° C., the pulse-release dosage form provides release of the API 1 P 2 and the API 2 P 2 beginning from 1 to 4 hours after release of the API 1 P 1 and the API 2 P 1 begins, and release of the API 1 P 3 and the API 2 P 3 beginning from 1 to 4 hours after release of the API 1 P 2 and the API 2 P 2 begins.
- the oral pulse-release dosage form may include the following details, which can be combined with one another in any combinations unless clearly mutually exclusive:
- the pulse-release dosage form may provide a second time of peak release rate (PRR 2 ) of each of the API 1 (PRR 2 API 1 ) and the API 2 (PRR 2 API 2 ) from about 1 to 4 hours after a first time of PRR (PRR 1 ) and a third time of peak release rate (PRR 3 ) of each of the API 1 (PRR 3 API 1 ) and the API 2 (PRR 3 API 2 ) from about 1 to 4 hours after the second time of PRR (PRR 2 ).
- PRR 2 second time of peak release rate of each of the API 1 (PRR 2 API 1 ) and the API 2 (PRR 2 API 2 ) from about 1 to 4 hours after a first time of PRR (PRR 1 )
- the PRR 1 may be after 1-2 hours.
- the first cannabinoid API 1 may be delta-9-tetrahydrocannabinol (THC) and the second cannabinoid API 2 may be cannabinol (CBN).
- THC delta-9-tetrahydrocannabinol
- CBN cannabinol
- the total daily dose of the THC may be from 10 mg to 40 mg and the total daily dose of the CBN may be from 5 mg to 100 mg.
- the first cannabinoid API 1 may be THC and the second cannabinoid API 2 may be CBN
- the total daily dose of the THC may be selected from: at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, and at least 35 mg
- the total daily dose of the CBN may be selected from: at least 5 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, and at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, and at least 95 mg.
- the first pulse-release component (C 1 ) may be an immediate release (IR) formulation of the first cannabinoid API 1 and the second cannabinoid API 2 , comprising the first portion (P 1 ) of the first cannabinoid API (API 1 P 1 ) and a first portion (P 1 ) of the second cannabinoid API (API 2 P 1 ).
- the first pulse-release component (C 1 ) may comprise one or more binders, one or more disintegrants, one or more lubricants, one or more flow aids, or any combinations thereof.
- the second pulse-release component (C 2 ) may be a delayed release (DR) formulation of the first cannabinoid API 1 and the second cannabinoid API 2 , comprising the second portion (P 2 ) of the first cannabinoid API (API 1 P 2 ) and a second portion (P 2 ) of the second cannabinoid API (API 2 P 2 ).
- the second pulse-release component (C 2 ) may comprise one or more binders, one or more lubricants, one or more flow aids, or any combinations thereof.
- the second pulse-release component may be coated with a first delayed-release layer comprising one or more pH-dependent and/or non-pH-dependent polymers, and optionally one or more plasticizers, one or more pore formers, one or lubricants, or any combinations thereof.
- the third pulse-release component (C 3 ) may be a delayed release (DR) formulation of the first cannabinoid API 1 and the second cannabinoid API 2 , comprising the third portion (P 3 ) of the first cannabinoid API (API 1 P 3 ) and a third portion (P 3 ) of the second cannabinoid API (API 2 P 3 ).
- DR delayed release
- the third pulse-release component (C 3 ) may comprise one or more binders, one or more lubricants, one or more flow aids, or any combinations thereof.
- the third pulse-release component may be coated with a second delayed-release layer comprising one or more pH-dependent and/or non-pH-dependent polymers, and optionally one or more plasticizers, one or more pore formers, one or lubricants, or any combinations thereof.
- the first portion (P 1 ) may be independently selected from 25% to 75% of the total daily dose
- the second portion (P 2 ) may be independently selected from 25% to 75% of the total daily dose
- the third portion (P 3 ) may be independently selected from 25% to 75% of the total daily dose.
- the binders may comprise from 1 to 60% (w/w)
- the disintegrants may comprise from 0.05 to 15% (w/w)
- the lubricants may comprise from 0.5 to 5% (w/w)
- the flow aids may comprise from 0.05 to 0.5% (w/w)
- the pH-dependent and/or non-pH-dependent polymers may comprise from 0.5 to 35% (w/w).
- the first pulse-release component (C 1 ) may comprise from 2.5 mg to 30 mg of the first cannabinoid active pharmaceutical ingredient (API 1 ), wherein the API 1 is THC, and from 1.25 mg 30 to 75 mg of the second cannabinoid active pharmaceutical ingredient (API 1 ), wherein the API 1 is CBN.
- the first pulse-release component (C 1 ) may comprise microcrystalline cellulose, hydroxypropylmethylcellulose, croscormellose sodium, magnesium stearate, or any combinations thereof.
- the second pulse-release component (C 2 ) may comprise from 2.5 mg to 30 mg of the first cannabinoid active pharmaceutical ingredient (API 1 ), wherein the API 1 is THC, and from 1.25 mg to 75 mg of the second cannabinoid active pharmaceutical ingredient (API 1 ), wherein the API 1 is CBN.
- the second pulse-release component (C 2 ) may comprise microcrystalline cellulose, cellulose acetate phthalate, magnesium stearate, or any combinations thereof.
- the third pulse-release component (C 3 ) may comprise from 2.5 mg to 30 mg of the first cannabinoid active pharmaceutical ingredient (API 1 ), wherein the API 1 is THC, and from 1.25 mg to 75 mg of the second cannabinoid active pharmaceutical ingredient (API 1 ), wherein the API 1 is CBN.
- the third pulse-release component (C 3 ) may comprise microcrystalline cellulose, methacrylic acid copolymer, magnesium stearate, or any combinations thereof.
- the present disclosure provides a method of treating a sleep disorder in a subject in need thereof, the method comprising: administering to the subject an oral pulse-release dosage form described herein.
- the method may include the following details, which can be combined with one another in any combinations unless clearly mutually exclusive:
- the administering may result in an increase in the subject's total sleeping time during the night.
- the administering may result in an increase in the subject's total light sleeping time during the night.
- the administering may result in an increase in the subject's light sleeping time as a proportion of total sleeping time during the night.
- the administering may result in an increase in the subject's total time in bed during the night.
- the increase may be measured using a SleepScore Max® system.
- the administering may result in an increase in SleepScore number as determined using a SleepScore Max® system.
- the administering may result in the subject experiencing an increase in one or more of: feeling well rested in the morning and/or during the day, perceived sleep quality, perceived total sleep time during the night, or sleep satisfaction. Additionally or alternatively, the subject may experience a decrease in one or more of: perceived frequency of awakenings during the night, number of times out of bed at night, number of naps during the day, or perceived time awake at night.
- the sleep disorder may comprise insomnia, wherein the insomnia is primarily characterized by an inability to stay asleep during the night.
- the insomnia may be characterized using a SleepScore Max® system.
- Characterization of the sleep disorder may be reported by the subject.
- the administering may not result in a decrease in latency to sleep onset, an alteration of time in deep sleep and/or REM sleep, a hangover effect during the day after the administering, or any combinations thereof.
- the subject may have previously been administered with one or more cannabinoids for treating a medical condition.
- the administering may be up to 30 minutes, 1 hour, or 2 hours before the subject intends to begin sleeping at night.
- FIG. 1 is a graph reporting an example in vitro dissolution release rate (g/mL per timepoint) of delta-9 Tetrahydrocannabinol (THC) versus time in hours of an example 2-pulse oral pharmaceutical composition tablet.
- THC delta-9 Tetrahydrocannabinol
- FIG. 2 is a graph reporting an example dissolution profile of cumulative release of % total THC dose versus time in hours of an example 2-pulse oral pharmaceutical composition tablet.
- FIG. 3 is a schematic showing an example clinical study timeline.
- FIG. 4 is a graph reporting example medical conditions for which cannabis was used. Up to 3 conditions could be selected by each participant.
- FIG. 5 is a graph reporting example sleep concerns of clinical trial participants prior to using an example pulse-release dosage form of the present disclosure. Percentages do not total 100 because multiple answers were allowed.
- FIG. 6 is a graph reporting example forms of cannabis being used by clinical trial participants to help with sleep prior to the product use period. Percentages do not total 100 because multiple answers were allowed.
- FIG. 7 is a graph reporting example data on self-reported average number of times participants woke up per night.
- FIG. 8 is a graph reporting example self-reported average amount of time per night spent awake after initially falling asleep.
- FIG. 9 is a graph reporting example self-reported average number of hours and minutes slept per night.
- FIG. 10 is a graph reporting example self-reported number of mornings per week participants woke up feeling well rested.
- FIG. 11 is a graph reporting example self-reported number of nights per week participants felt satisfied with their sleep.
- FIG. 12 is a graph reporting example self-reported number of days per week participants napped.
- FIG. 13 is a schematic showing an example clinical study timeline.
- FIG. 14 is a graph reporting example medical conditions for which cannabis was used. Up to 3 conditions could be selected by each participant.
- FIG. 15 is a graph reporting example sleep concerns of clinical trial participants prior to using an example pulse-release dosage form of the present disclosure. Percentages do not total 100 because multiple answers were allowed.
- FIG. 16 is a graph reporting example forms of cannabis being used by clinical trial participants to help with sleep prior to the product use period. Percentages do not total 100 because multiple answers were allowed.
- FIG. 17 is a graph reporting example data on self-reported average number of days per week participants felt so sleepy/tired that it affected them at school/work or in their private life. Note: * indicates significant at p ⁇ 0.05 after 1 week of use. ** indicates significant at p ⁇ 0.05 after 3 weeks of use.
- FIG. 18 is a graph reporting example data on self-reported average sleepiness of participants at bedtime. Note: ** indicates significant at p ⁇ 0.05 after 3 weeks of use.
- FIG. 19 is a graph reporting example data on self-reported average number of nights per week participants reported falling asleep in the amount of time that they preferred. Note: ** indicates significant at p ⁇ 0.05 after 3 weeks of use.
- FIG. 20 is a graph reporting example data on self-reported average number of minutes it took to fall asleep per night.
- FIG. 21 is a graph reporting example data on self-reported average number of mornings per week participants woke up feeling well rested. Note: ** indicates significant at p ⁇ 0.05 after 3 weeks of use.
- FIG. 22 is a graph reporting example data on self-reported average number of nights per week participants felt satisfied with their sleep. Note: ** indicates significant at p ⁇ 0.05 after 3 weeks of use.
- Insomnia defined as difficulty falling asleep or staying asleep, is the most common sleep disorder with approximately 30% of adults having symptoms each year (National Sleep Foundation. What is Insomnia? https://www.sleepfoundation.org/insomnia/what-insomnia, Accessed 2019; The American Academy of Sleep Medicine. Insomnia. https://aasm.org/resources/factsheets/insomnia.pdf, Accessed 2019). It is a major contributing factor to motor vehicle deaths, and loss of productivity, due to insomnia, costs the US workforce $63.2 billion annually (The American Academy of Sleep Medicine. Insomnia.
- THC Delta-9 Tetrahydrocannabinol
- the present disclosure relates to oral cannabinoid pharmaceutical compositions and methods of treating sleep disorders using the oral cannabinoid pharmaceutical compositions.
- API's Active Pharmaceutical Ingredients
- an API of the present disclosure can be a cannabinoid.
- cannabinoid refers to several classes of compounds that can be found in plants of the genus Cannabis . There are at least 144 different cannabinoids that have been isolated from cannabis , exhibiting varied effects. Synthetic encompass a variety of distinct chemical classes: the classical cannabinoids structurally related to THC, the nonclassical cannabinoids (cannabimimetics) including the aminoalkylindoles, 1,5-diarylpyrazoles, quinolines, and arylsulfonamides as well as eicosanoids related to endocannabinoids.
- the classical cannabinoids are concentrated in a viscous resin of cannabis plants produced in structures known as glandular trichomes.
- the main classes of cannabinoids include, without limitation, THC (tetrahydrocannabinol), THCA (tetrahydrocannabinolic acid), CBD (cannabidiol), CBDA (cannabidiolic acid), CBN (cannabinol), CBG (cannabigerol), CBC (cannabichromene), CBL (cannabicyclol), CBV (cannabivarin), THCC (tetrahydrocannabiorcol), THCV (tetrahydrocannabivarin), THCP (tetrahydrocannabiphorol), CBDV (cannabidivarin), CBCV (cannabichromevarin), CBGV (cannabigerovarin), CBGM (cannabigerol monomethyl ether), CBE (cannabielsoin), and CBT (cannabicitran
- Cannabinoids of the present disclosure include, without limitation: Cannabigerol-type (CBG) cannabinoids, such as Cannabigerol monomethyl ether, Cannabinerolic acid A, Cannabigerovarin, Cannabigerolic acid A, Cannabigerolic acid A monomethyl ether, and Cannabigerovarinic acid A; Cannabichromene-type (CBC) cannabinoids, such as ( ⁇ )-Cannabichromene, ( ⁇ )-Cannabichromenic acid A, ( ⁇ )-Cannabivarichromene, ( ⁇ )-Cannabichromevarin, and ( ⁇ )-Cannabichromevarinic acid A; Cannabidiol-type (CBD) cannabinoids, such as ( ⁇ )-Cannabidiol, Cannabidiol momomethyl ether, Cannabidiol-C 4 , ( ⁇ )-Cannabidivarin, Cannabidiorcol, Cannabidio
- the term “cannabinoid” as used herein refers to compounds that may be extracted from, and/or derived from Cannabis plants using methods known in the art.
- cannabinoids can be separated from the cannabis plant by extraction with organic solvents or using supercritical solvent extraction with carbon dioxide.
- Cannabinoids may be obtained in oils extracted from cannabis plants, and thereafter further isolated, purified, and converted into derivatives.
- the term “cannabinoid” as used herein may also refer to such compounds that may be produced synthetically or using recombinant biotechnology methods, as may be identified by persons of ordinary skill in the art.
- Cannabinoids of the present disclosure may include stereoisomers thereof, and modified forms thereof, such as a pharmaceutically acceptable salt, ester, derivative, analog, prodrug, hydrate, or solvate thereof.
- a pharmaceutical compositions of the present disclosure can include, without limitation, one or more cannabinoids, two or more cannabinoids, or three or more cannabinoids.
- the cannabinoid may be THC, CBN, CBD, or any combinations thereof.
- cannabinoids include tetrahydrocannabinol (THC), cannabidiol (CBD) and cannabinol (CBN).
- THC tetrahydrocannabinol
- CBD cannabidiol
- CBN cannabinol
- ⁇ 9 - tetrahydrocannabinol ⁇ 9 -THC or THC
- INN International Non-Proprietary Name
- THC isomer ( ⁇ )-(6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol.
- Two related substances, ⁇ 9 - tetrahydrocannabinol-2-oic acid and ⁇ 9 -tetrahydrocannabinol-4-oic acid (THCA) are also present in cannabis , sometimes in large amounts.
- THCA is partly converted to THC.
- Other closely related substances that occur in cannabis include cannabidiol (CBD) and, in aged samples, cannabinol (CBN), both of which have quite different pharmacological effects to THC.
- CBD cannabidiol
- CBN cannabino
- THC is the most known active component of cannabis .
- the pharmacology of cannabis is complicated by the presence of a wide range of cannabinoids.
- cannabis produces euphoria, relief of anxiety, sedation and drowsiness. In some respects, the effects are similar to those caused by alcohol.
- Anandamide has been identified as the endogenous ligand for the cannabinoid receptor and has pharmacological properties similar to those of THC.
- THC can be detected in plasma within seconds of inhalation; it has a half-life of 2 hours. Following smoking of the equivalent of 10-15 mg over a period of 5-7 minutes, peak plasma levels of ⁇ 9 -THC are around 100 ⁇ g/L.
- Bioavailability following the smoking route was reported as 2-56%, due in part to intra- and inter-subject variability in smoking dynamics, which contributes to uncertainty in dose delivery.
- the number, duration, and spacing of puffs, hold time, and inhalation volume, or smoking topography greatly influences the degree of drug exposure (Huestis M., “Human Cannabinoid Pharmacokinetics” Chem Biodivers. 2007 August; 4(8): 1770-1804).
- CBN-type cannabinoids are known. With ring A aromatized, they may be formed as oxidation artifacts of THC and CBD, respectively. Their concentration in cannabis products may depend on age and storage conditions. CBN has been shown to induce drowsiness, and reduced time to sleep, but has been shown to create “hangover” symptoms when used alone for sleep.
- THC and CBN are known to be readily absorbed via the inhalation route, but very little is known about the biotransformation of CBN following oral administration and release in the gastrointestinal tract. Furthermore, to date, very little, if any, published information is available regarding the extent, or components of, biotransformation of cannabinoids, such as THC or CBN, following a delayed-release e.g. into the duodenum.
- compositions described herein are provided to meet the need in the art for oral dosage forms that provide controlled release into the gastrointestinal tract of a subject, in order to provide delivery of cannabinoid APIs described herein that in some embodiments may be useful for treating sleep disorders.
- the present disclosure provides oral pulse-release compositions and dosage forms thereof, comprising a dose, e.g. a total daily dose, of one or more cannabinoid active pharmaceutical ingredients.
- pulse-release or “pulsatile” formulation, as used herein refers in general to release of a portion of a total API dose, e.g. a portion of a total daily API dose, in a burst, followed by periods of little or no release (e.g., lag phase) in a defined temporal pattern.
- oral pulsatile drug release pertains to the burst delivery of drugs following a temporal pattern from the time of oral administration.
- the pulse-release formulations of the present disclosure may combine a range of formulation approaches, including single- or multiple-unit immediate-release, delayed-release, and/or extended-release components.
- the delayed release components in the pulsatile formulations described herein may be configured to release an API at a desired site within the gastrointestinal tract, and/or release of the API after a defined time period.
- an oral pulse-release dosage form of the present disclosure may comprise one or more immediate release oral pharmaceutical formulation components, one or more delayed release oral pharmaceutical formulation components, one or more extended release oral pharmaceutical formulation components, or any combinations thereof.
- an oral pulse-release dosage form of the present disclosure when administered orally to a subject, is configured to provide release of a dosage, e.g. a daily dosage, of the one or more cannabinoids into the gastrointestinal tract of the subject, divided into at least 2 separate releases, or pulses separated by at least 2 hours, and not more than 6 hours, between releases.
- an oral pulse-release dosage form of the present disclosure when administered orally to a subject, is configured to provide release of a dosage, e.g. a daily dosage, of the one or more cannabinoids into the gastrointestinal tract of the subject, divided into at least 3 separate releases, or pulses separated by at least 1 hours, and not more than 4 hours, between releases.
- an oral pulse-release dosage form of the present disclosure may provide a total daily dose of a cannabinoid API, or a partial daily dose of a cannabinoid API.
- a plurality, e.g. 2, 3, or more of the oral pulse-release dosage form of the present disclosure may be administered to a subject to provide a total daily dose.
- the oral pulse-release dosage form of the present disclosure may be administered once, twice, three times or more, per day to provide a total daily dose of a cannabinoid API.
- the pulse-release dosage forms of the present disclosure are configured to release a portion of an API in the gastric region (e.g. in the stomach), and the remaining portion in the small intestine e.g. distal duodenum, or other distal sites in the gastrointestinal tract.
- the present disclosure provides an oral pulse-release dosage form, comprising a total dose, e.g. a total daily dose, of a cannabinoid active pharmaceutical ingredient (API), wherein the pulse-release dosage form comprises a first pulse-release component (C 1 ) comprising a first portion (P 1 ) of the cannabinoid API (API-P 1 ), and at least a second pulse-release component (C 2 ) comprising a second portion (P 2 ) of the first cannabinoid API (API 1 P 2 ).
- the total dose e.g.
- the pulse-release dosage form When the pulse-release dosage form is placed in a simulated gastrointestinal environment, the pulse-release dosage form provides release of the API-P 2 beginning from 2 to 6 hours after release of the API-P 1 begins.
- simulated gastrointestinal environment is intended to be used herein to convey its ordinary meaning as understood in the art, and is understood in a broad sense to mean conditions that mimic oral administration, for example, an aqueous environment of low pH, 1-5 for example, followed after a period of up to about 2 hours with immersion in a higher pH aqueous environment, such as pH 6.8, for example, or a 3 stage environment in which the low pH is followed by an intermediate pH of about 6 wherein the environments are maintained at about 37.0° C.
- a simulated gastrointestinal environment is described as the USP Apparatus I (Baskets) with agitation in which the composition is placed in 700 ml aqueous solution of 0.1N HCl pH 1.1, for up to 2 hours followed by 2-8 hours in sodium phosphate buffer at pH 6.0; followed by 6-20 hours in sodium phosphate buffer, pH 7.2, adding NaOH to adjust pH to 7.2.
- the dissolution testing can include placing a dosage form in an aqueous solution of 0.1N HCl pH 1.1 for 2 hours followed by 8 hours in sodium phosphate buffer at pH 6.8, at 37° C. ⁇ 0.5° C., and sampling at appropriate time intervals, e.g. at 1, 1.5, 2, 3, 3.5, 4, 5, 6, 7, 8, 9 and 10 hours.
- a two-stage dissolution test is described in USP General Chapter ⁇ 711>Dissolution, in which the integrity of an enteric coating is determined in an acidic environment and the drug release is measured in a neutral environment.
- the test can be performed using either medium-addition or medium exchange methods; both may start with an acid stage in 0.1 N hydrochloric acid for two hours and follow with a buffer stage in phosphate buffer at pH 6.8 for e.g. 45 min or a specific time as needed for the individual drug product.
- Medium addition or medium exchange procedures may be used.
- a designated amount of concentrated phosphate buffer may be added to the dissolution vessel to neutralize the medium to the target pH before the buffer stage starts.
- the operations of adding the buffer and adjusting the pH may be completed within 5 min.
- the acid medium may be drained after two hours, and a full amount of pH 6.8 buffer may be added to the same vessel for the buffer stage.
- the dosage unit is typically left undisturbed during the medium change.
- the vessel containing the acid can be removed and replaced with another vessel containing the buffer, and the dosage unit transferred to the new vessel.
- API-specific biorelevant dissolution methods such as in vitro dissolution analysis can be determined by skilled persons without undue experimentation upon reading the present disclosure.
- an in-vitro non-sink, gastric transfer dissolution method may be used to analyze the release and dissolution of API.
- samples may be drawn from the dissolution vessel and centrifuged using an ultracentrifuge.
- the supernatants may be further diluted using an HPLC diluent and analyzed by a suitable HPLC method.
- Parameters such as peak release rate (PRR) and the area under drug dissolution curve (AUDC), among others, may be calculated, e.g. by the linear trapezoidal method.
- Each of the pulse-release components that may be combined to provide the oral pulse-release dosage form may be analyzed separately by in vitro dissolution tests, to determine the pulse-release timing for each pulse-release component of the oral pulse-release dosage form.
- the “beginning” of release from a pulse-release component may be defined as the time at which a detectable amount of the API is present in the dissolution media, or when a certain percentage of the total dose is detected in the dissolution media, e.g. at least 1%, 5%, or 10% of the total amount of the API present in the particular pulse-release component.
- the simulated gastrointestinal environment may be an aqueous solution of 0.1N HCl pH 1.1 for 2 hours followed by 8 hours in sodium phosphate buffer at pH6.8, at 37° C. ⁇ 0.5° C.
- the pulse-release dosage form when the pulse-release dosage form is placed in a simulated gastrointestinal environment, the pulse-release dosage form may provide a second time of peak release rate (PRR 2 ) of the API from about 2 to 6 hours after a first time of peak release rate (PRR 1 ).
- PRR 2 peak release rate
- PRR 1 first time of peak release rate
- FIG. 1 and Example 3 describe example in vitro dissolution data of an example pulse-release dosage form of the present disclosure.
- a first time of PRR of the API when the pulse-release dosage form is placed in a simulated gastrointestinal environment, a first time of PRR of the API may be after 1-2 hours, and a second time of PRR may be from about 2 to 6 hours after the first time of PRR.
- the pulse-release dosage form may comprise a total dose, e.g. a total daily dose, of a cannabinoid API from 1 mg to 100 mg, for example, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 mg.
- a total daily dose
- the first pulse-release component (C 1 ) may be an immediate release (IR) formulation of the cannabinoid API.
- an IR formulation of the API may include, without limitation, the first portion (P 1 ) of the cannabinoid API (API-P 1 ), as well as one or more binders, one or more disintegrants, one or more lubricants, one or more flow aids, or any combinations thereof.
- the second pulse-release component (C 2 ) may be a delayed release (DR) formulation of the cannabinoid API.
- a DR formulation of the API may include, without limitation, the second portion (P 2 ) of the cannabinoid API (API-P 2 ), as well as one or more binders, one or more lubricants, one or more flow aids, or any combinations thereof, and the second pulse-release component may be coated with a layer of one or more pH-dependent or non-pH-dependent polymers, one or more plasticizers, or both.
- the second pulse-release component may be coated with a layer of one or more pH-dependent or non-pH-dependent polymers, one or more plasticizers, or both.
- the binder may include, but is not limited to, microcrystalline cellulose, corn starch, pregelatinized starch, potato starch, rice starch, sodium carboxymethyl starch, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, ethylcellulose, chitosan, hydroxychitosan, hydroxymethylatedchitosan, cross-linked chitosan, cross-linked hydroxymethyl chitosan, maltodextrin, mannitol, sorbitol, dextrose, maltose, fructose, glucose, levulose, sucrose, polyvinylpyrrolidone (PVP), acrylic acid derivatives (Carbopol, Eudragit, etc.), polyethylene glycols, such a low molecular weight PEGs (PEG2000-10000) and high molecular weight PEGs (Polyox) with molecular weights above 20,000 daltons.
- PEG2000-10000 low molecular weight
- the binders may be present in a pulse-release component of the pulse-release dosage form in the range of 1.0 to 60% (W/W).
- ingredients that may be included in a pulse-release component of the pulse-release dosage form to aid in the dissolution of the API, or the breakdown of the pulse-release component after ingestion or administration may include, without limitation, one or more surfactants, such as sodium lauryl sulfate, sodium monoglycerate, sorbitan monooleate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, glyceryl monostearate, glyceryl monooleate, glyceryl monobutyrate, a non-ionic surfactant such as the Pluronic line of surfactants, or any other material with surface active properties.
- surfactants such as sodium lauryl sulfate, sodium monoglycerate, sorbitan monooleate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, glyceryl monostearate, glyceryl monooleate, glyceryl monobutyrate, a non-i
- the disintegrant may include, but is not limited to, sodium starch glycolate, corn starch, rice starch, gar gum, polyvinylpolypyrrolidone, croscarmellose, and hydroxypropylmethylcellulose, among others.
- the disintegrants may be present in a pulse-release component of the pulse-release dosage form in the range of 0.05-15% (W/W).
- the lubricant may include, but is not limited to, magnesium stearate, calcium stearate, and stearic acid, among others.
- the lubricants may be present in a pulse-release component of the pulse-release dosage form in the range of 0.05-5% (W/W).
- the flow aid may include, but is not limited to, colloidal silicone dioxide, and magnesium stearate, among others.
- the flow aids may be present in a pulse-release component of the pulse-release dosage form in the range of 0.05-0.5% (W/W).
- the polymer coating may include, but is not limited to, one or more pH-dependent or non-pH-dependent excipients.
- non-pH dependent polymers include ethyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, copolymer of ethyl acrylate, methyl methacrylate (e.g., Eudragit R S), among others.
- pH-dependent excipients include methacrylic acid copolymers, hydroxypropylmethyl cellulose acetate succinate, hydroxypropylmethyl cellulose phthalate, and cellulose acetate phthalate, among others.
- the pH-dependent polymer coating may also include a pore former, such as povidone, polyethylene glycol, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, among others, sugars such as sucrose, mannitol, lactose, and salts, such as sodium chloride, sodium citrate, among others.
- the polymer coating may include a plasticizer, such as acetylated citrated esters, acetylated glycerides, castor oil, citrate esters, dibutylsebacate, glyceryl monostearate, diethyl phthalate, glycerol, medium chain triglycerides, propylene glycol, and polyethylene glycol.
- the coating may also include one or more additional excipients, such as lubricants (e.g., magnesium stearate, talc among others).
- the coating can be applied using conventional coating techniques such as fluidized bed coating, pan coating, among others.
- the pH-dependent polymer can be a pharmaceutically acceptable acrylic polymer, including but not limited to, acrylic acid and methacrylic acid copolymers, methyl methacrylate, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid), poly (methacrylic acid), methacrylic acid alkylamine copolymer poly(methyl methacrylate), poly(methacrylic acid)(anhy-dride), polymethacrylate, polyacrylamide, poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers.
- acrylic acid and methacrylic acid copolymers including but not limited to, acrylic acid and methacrylic acid copolymers, methyl methacrylate, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl meth
- the acrylic polymer is comprised of one or more ammonia methacrylate copolymers.
- Ammonio methacrylate copolymers are well known in the art, and are described as fully polymerized copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups.
- the acrylic polymer may be an acrylic resin lacquer such as a Eudragit®.
- the acrylic polymer comprises a mixture of two acrylic resin lacquers commercially available from Evonik/Rohm Pharma under the trade names Eudragit® RL30D and Eudragit® RS30D, respectively.
- Eudragit® RL30D and Eudragit® RS30D are copolymers of acrylic and methacrylic esters with a low content of quaternary ammonium groups, the molar ratio of ammonium groups to the remaining neutral (meth)acrylic esters being 1:20 in Eudragit® RL30D and 1:40 in Eudragit® RS30D.
- Eudragit® S-100 and Eudragit® L-100 are also suitable for use herein.
- the code designations RL (high permeability) and RS (low permeability) refer to the permeability properties of these agents.
- Eudragit® mixtures are insoluble in water and in digestive fluids.
- multi-particulate systems formed to include the same are swellable and permeable in aqueous solutions and digestive fluids.
- the polymers described above such as Eudragit® RL/RS may be mixed together in any desired ratio in order to ultimately obtain an extended release formulation having a desirable dissolution profile.
- acrylic polymers may also be used, such as, for example, Eudragit® L.
- the polymer coatings may be present in a pulse-release component of the pulse-release dosage form in the range of 0.5-35% (W/W).
- the pulse-release dosage form may include API coated cores.
- the cores may comprise non-pareils or sugar spheres.
- the pulse-release dosage form may optionally comprise a seal coat.
- a DR pulse-release component of the pulse-release dosage form may be coated with a polymer coating by fluidized bed coating.
- a pulse-release component of the present disclosure can be prepared by any suitable method known in the art, such as mixing the ingredients in a suitable pharmaceutical mixer or granulator such as a planetary mixer, high-shear granulator, fluid bed granulator, or extruder, in the presence of water or other solvent, or in a hot melt process. If water or other solvent is used, the blend may be dried in a suitable pharmaceutical drier, such as a vacuum oven or forced-air oven. After allowing the product to cool, the product may be sieved or granulated, and compressed using a suitable tablet press, such as a rotary tablet press.
- a suitable pharmaceutical drier such as a vacuum oven or forced-air oven.
- a pharmaceutical formulation of the present disclosure may be further processed into a solid dosage form suitable for oral administration, such as a pill, tablet or capsule.
- the pharmaceutical formulation of the present disclosure may be provided in oral dosage forms such as a syrup, film, orally-disintegrating tablet, a liquid solution or suspension (e.g., drink or syrup), a powder, or liquid or solid crystals, or a paste.
- Example 2 An example method of formulating an example pulse-release oral dosage form of the present disclosure is described in Example 2.
- the percentage of API released from the first portion (P 1 ) may be from 25% to 75% of the total dose, e.g. the total daily dose, and the percentage of API released from the second portion (P 2 ) may be from 25% to 75% of the total dose, e.g. the total daily dose.
- the cannabinoid API may be THC. In certain embodiments, the cannabinoid API may be CBN.
- the first pulse-release component (C 1 ) may include from at least 2.5 mg to at least 30 mg THC. In some embodiments, in the oral pulse-release dosage form, the first pulse-release component (C 1 ) may include from at least 1.25 mg to at least 75 mg CBN. In some embodiments, in the oral pulse-release dosage form, the second pulse-release component (C 2 ) may include from at least 2.5 mg to at least 30 mg THC. In some embodiments, in the oral pulse-release dosage form, the second pulse-release component (C 2 ) may include from at least 1.25 mg to at least 75 mg CBN.
- the oral pulse-release dosage form of the present disclosure may include a first cannabinoid API and a second cannabinoid API. Accordingly, in some embodiments, the oral pulse-release dosage form may include a total dose, e.g.
- a first pulse-release component (C 1 ) comprising a first portion (P 1 ) of the first cannabinoid API (API 1 P 1 ) and a first portion (P 1 ) of the second
- the total dose e.g the total daily dose of each of the API 1 and the API 2 is divided between the first portion (P 1 ) in the first pulse-release component (C 1 ) and at least the second portion (P 2 ) in the at least second pulse-release component (C 2 ).
- the pulse-release dosage form When the pulse-release dosage form is placed in a simulated gastrointestinal environment, e.g. an aqueous solution of 0.1N HCl pH 1.1 for 2 hours followed by 8 hours in sodium phosphate buffer at pH 6.8, at 37° C. ⁇ 0.5° C., the pulse-release dosage form provides release of the API 1 P 2 and the API 2 P 2 beginning from 2 to 6 hours after release of the API 1 P 1 and the API 2 P 1 begins.
- the pulse-release dosage form when the pulse-release dosage form is placed in a simulated gastrointestinal environment, the pulse-release dosage form may provide a second time of peak release rate (PRR 2 ) of each of the API 1 (PRR 2 API 1 ) and the API 2 (PRR 2 API 2 ) from about 2 to 6 hours after a first time of peak release rate (PRR 1 ). In some embodiments, the PRR 1 may be after 1-2 hours.
- the first cannabinoid API 1 may be THC and the second cannabinoid API 2 may be cannabinol (CBN), and the total dose, e.g. the total daily dose, of the THC is from 1 mg to 40 mg and the total dose, e.g. the total daily dose of the CBN is from 2.5 mg to 100 mg.
- the total dose, e.g. the total daily dose, of the THC is from 1 mg to 40 mg and the total dose, e.g. the total daily dose of the CBN is from 2.5 mg to 100 mg.
- the first cannabinoid API 1 may be THC and the second cannabinoid API 2 may be CBN, and the total dose, e.g. the total daily dose, of the THC is selected from: at least 1 mg, at least 2 mg, at least 3 mg, at least 4 mg, at least 5 mg, at least 6 mg, at least 8 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, and at least 35 mg, and the total dose e.g.
- the total daily dose, of the CBN is selected from: at least 2.5 mg, at least 3 mg, at least 4 mg, at least 5 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, and at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, and at least 95 mg.
- the first pulse-release component (C 1 ) may be an immediate release (IR) formulation of the first cannabinoid API 1 and the second cannabinoid API 2 , comprising the first portion (P 1 ) of the first cannabinoid API (API 1 P 1 ) and the first portion (P 1 ) of the second cannabinoid API (API 2 P 1 ).
- IR immediate release
- the second pulse-release component (C 2 ) may be a delayed release (DR) formulation of the first cannabinoid API 1 and the second cannabinoid API 2 , comprising the second portion (P 2 ) of the first cannabinoid API (API 1 P 2 ) and a second portion (P 2 ) of the second cannabinoid API (API 2 P 2 ).
- DR delayed release
- the first portion (P 1 ) may be independently selected from 25% to 75% of the total dose, e.g. the total daily dose
- the second portion (P 2 ) may be independently selected from 25% to 75% of the total dose, e.g. the total daily dose.
- the first pulse-release component (C 1 ) may comprise from 0.5 mg to 30 mg of the first cannabinoid active pharmaceutical ingredient (API 1 ), wherein the API 1 is THC, and from 1.25 mg to 75 mg of the second cannabinoid active pharmaceutical ingredient (API 1 ), wherein the API 1 is CBN.
- the second pulse-release component (C 2 ) may comprise from 0.5 mg to 30 mg of the first cannabinoid active pharmaceutical ingredient (API 1 ), wherein the API 1 is THC, and from 1.25 mg to 75 mg of the second cannabinoid active pharmaceutical ingredient (API 1 ), wherein the API 1 is CBN.
- the daily dosage is at least 1 mg THC and at least 10 mg CBN. In some embodiments, the daily dosage is at least 2 mg THC and at least 20 mg CBN. In some embodiments, the daily dosage is at least 4 mg THC and at least 40 mg CBN. In some embodiments, the daily dosage is at least 5 mg THC and at least 2.5 mg CBN. In some embodiments, the daily dosage is at least 6 mg THC and at least 3 mg CBN. In some embodiments, the daily dosage is at least 8 mg THC and at least 4 mg CBN. In some embodiments, the daily dosage is at least 5 mg THC and at least 10 mg CBN. In some embodiments, the daily dosage is at least 10 mg THC and at least 10 mg CBN.
- the daily dosage is at least 20 mg THC and at least 10 mg CBN. In some embodiments, the daily dosage is at least 20 mg THC and at least 20 mg CBN. In some embodiments, the daily dosage is at least 10 mg THC and at least 20 mg CBN. In some embodiments, the daily dosage is at least 10 mg THC and at least 25 mg CBN. In some embodiments, the daily dosage is at least 10 mg THC and at least 30 mg CBN. In some embodiments, the daily dosage is at least 10 mg THC and at least 40 mg CBN.
- Example formulations of the pulse-release oral dosage forms of the present disclosure are provided in Example 1.
- the oral pulse-release dosage form comprises a total dose e.g. a total daily dose of a first cannabinoid active pharmaceutical ingredient (API 1 ) and a total dose e.g. a total daily dose of a second cannabinoid API (API 2 ), wherein the pulse-release dosage form comprises a first pulse-release component (C 1 ) comprising a first portion (P 1 ) of the first cannabinoid API (API 1 P 1 ) and a first portion (P 1 ) of the second cannabinoid API (API 2 P 1 ), a second pulse-release component (C 2 ) comprising a second portion (P 2 ) of the first cannabinoid API (API 1 P 2 ) and a second portion (P 2 ) of the second cannabinoid API (API 2 P 2 ), and at least a third pulse-release component (C 3 ) comprising a third portion (P 3 ) of the first cannabinoid API (
- the total dose e.g. the total daily dose of each of the API 1 and the API 2 is divided between the first portion (P 1 ) in the first pulse-release component (C 1 ), the second portion (P 2 ) in the second pulse-release component (C 2 ), and at least the third portion (P 3 ) in the at least third pulse-release component (C 3 ).
- the pulse-release dosage form When the pulse-release dosage form is placed in an aqueous solution of 0.1N HCl pH 1.1 for 2 hours followed by 8 hours in sodium phosphate buffer at pH 6.8, at 37° C. ⁇ 0.5° C., the pulse-release dosage form provides release of the API 1 P 2 and the API 2 P 2 beginning from 1 to 4 hours after release of the API 1 P 1 and the API 2 P 1 begins, and release of the API 1 P 3 and the API 2 P 3 beginning from 1 to 4 hours after release of the API 1 P 2 and the API 2 P 2 begins.
- the oral pulse-release dosage form provides a second time of peak release rate (PRR 2 ) of each of the API 1 (PRR 2 API 1 ) and the API 2 (PRR 2 API 2 ) from about 1 to 4 hours after a first time of peak release rate (PRR 1 ) and a third time of peak release rate (PRR 3 ) of each of the API 1 (PRR 3 API 1 ) and the API 2 (PRR 3 API 2 ) from about 1 to 4 hours after the second time of peak release rate (PRR 2 ).
- the PRR 1 is after 1-2 hours.
- the first cannabinoid API 1 when the oral pulse-release dosage form provides release of a dosage, e.g. a daily dosage, of the API 1 and the API 2 into the gastrointestinal tract of the subject, divided into at least 3 separate releases, the first cannabinoid API 1 may be THC and the second cannabinoid API 2 may be CBN.
- the total dose, e.g. the total daily dose, of the THC may be from 10 mg to 40 mg and the total dose e.g. the total daily dose of the CBN may be from 5 mg to 100 mg.
- the first cannabinoid API 1 is THC and the second cannabinoid API 2 is CBN, and the total dose e.g.
- the total daily dose of the THC is selected from: at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, and at least 35 mg
- the total dose e.g. the total daily dose of the CBN is selected from: at least 5 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, and at least 95 mg.
- the first pulse-release component (C 1 ) may be an immediate release (IR) formulation of the first cannabinoid API 1 and the second cannabinoid API 2 , comprising the first portion (P 1 ) of the first cannabinoid API (API 1 P 1 ) and a first portion (P 1 ) of the second cannabinoid API (API 2 P 1 ).
- IR immediate release
- the second pulse-release component (C 2 ) may be a delayed release (DR) formulation of the first cannabinoid API 1 and the second cannabinoid API 2 , comprising the second portion (P 2 ) of the first cannabinoid API (API 1 P 2 ) and a second portion (P 2 ) of the second cannabinoid API (API 2 P 2 ).
- DR delayed release
- the third pulse-release component (C 3 ) may be a delayed release (DR) formulation of the first cannabinoid API 1 and the second cannabinoid API 2 , comprising the third portion (P 3 ) of the first cannabinoid API (API 1 P 3 ) and a third portion (P 3 ) of the second cannabinoid API (API 2 P 3 ).
- the second pulse-release component may be coated with a first delayed-release layer comprising one or more pH-dependent and/or non-pH-dependent polymers, and optionally one or more plasticizers, one or more pore formers, and/or one or lubricants.
- the third pulse-release component may be coated with a second delayed-release layer comprising one or more pH-dependent and/or non-pH-dependent polymers, and optionally one or more plasticizers, one or more pore formers, and/or one or lubricants.
- the second delayed-release layer may provide a delayed release of 1-4 hours longer than the first delayed-release layer.
- the first portion (P 1 ) may be independently selected from 25% to 75% of the total dose e.g. the total daily dose
- the second portion (P 2 ) may be independently selected from 25% to 75% of the total dose e.g. the total daily dose
- the third portion (P 3 ) may be independently selected from 25% to 75% of the total dose e.g. the total daily dose.
- the first pulse-release component (C 1 ) may include from 2.5 mg to 30 mg of the first cannabinoid active pharmaceutical ingredient (API 1 ), wherein the API 1 is THC, and from at least 1.25 mg to 75 mg of the second cannabinoid active pharmaceutical ingredient (API 1 ), wherein the API 1 is CBN.
- the second pulse-release component (C 2 ) may include from 2.5 mg to 30 mg of the first cannabinoid active pharmaceutical ingredient (API 1 ), wherein the API 1 is THC, and from 1.25 mg to 75 mg of the second cannabinoid active pharmaceutical ingredient (API 1 ), wherein the API 1 is CBN.
- the third pulse-release component (C 3 ) may include from 2.5 mg to 30 mg of the first cannabinoid active pharmaceutical ingredient (API 1 ), wherein the API 1 is THC, and from 1.25 mg to 75 mg of the second cannabinoid active pharmaceutical ingredient (API 1 ), wherein the API 1 is CBN.
- the present disclosure provides a method of treating a sleep disorder in a subject in need thereof, the method comprising administering to the subject an oral pulse-release dosage form of the present disclosure.
- the administering may be up to 30 minutes, up to 1 hour, or up to 2 hours before the subject intends to begin sleeping at night.
- the description herein is primarily directed to treatment of sleep disorders in subjects with a typical schedule, wherein the subject intends to go to sleep starting from around 9 P.M. to about midnight, for example. Accordingly, terms used herein such as “at night”, “during the night” and so on are intended to refer to the usual period of time when the subject intends to be asleep, and, similarly, terms such as “in the morning” are intended to refer to a period after the subject's usual sleeping time. It is understood, however, that the use and efficacy of the compositions and methods described herein, is not limited to such a schedule, but can be adopted for use with different daily schedules, such as night workers, or people with more variable sleep patterns.
- the term sleep disorder as used herein more particularly refers to insomnia.
- Insomnia may include a difficulty falling asleep or staying asleep, or both.
- the sleep disorder may be characterized primarily or predominantly by various symptoms, such as difficulty falling asleep or may be characterized primarily or predominantly by difficulty staying asleep, either in an individual subject, or in a group of subjects, such as a population of subjects.
- the sleep disorder may include, without limitation, one or more of insufficient total sleeping time during the night, increased frequency of awakenings during the night, increased number of times out of bed at night, increased time awake at night, increased latency to sleep onset, deviations from proportions of time or duration of time in light sleep, deep sleep and/or REM sleep compared to those typically seen in individuals that do not experience insomnia, and the insomnia may produce a number of effects, such as not feeling well rested in the morning and/or during the day, decreased sleep satisfaction, increase in number of naps during the day, decreased wakefulness during daytime activities such as during work or school, or any combinations thereof.
- administering a subject in need of treatment for a sleep disorder with an oral pulse-release dosage form of the present disclosure may provide effective treatment of one or more aspects of the subject's sleep disorder.
- an example pulse-release dosage form comprising two example cannabinoid API's, THC and CBN provided effective treatment of insomnia in a group of subjects.
- the subjects in the study described in Example 4 experienced insomnia, primarily or predominantly characterized by difficulty staying asleep at night.
- Traditional sleep aids were marginally effective, and had a profound impact on quality of sleep, and in particular REM and deep sleep components of their sleep experience.
- the example formulation provided the subjects with longer sleep duration, and no deleterious effects on REM and deep sleep components of the sleep experience.
- the subjects experienced few residual effects (or “hangover”) of the treatment. This is in stark contrast to other drugs commonly used for sleep disorders
- the treatment did not affect all aspects of the subjects' sleep experience equally. For example, there was no effect on objective measures of latency to sleep onset, number of awakenings during the night, and no increase in time in REM sleep or deep sleep.
- Example 5 administering subjects reporting difficulty in falling asleep with the same dosage of 10 mg THC and 5 mg CBN, but delivered in an immediate release dosage form via the sublingual route, did not result in any objectively measured improvements in any aspect of sleep.
- 10 mg THC and 5 mg CBN delivered in an immediate release dosage form via the sublingual route significantly increased the time to fall asleep in these subjects.
- cannabinoids not all administration routes or dosage forms of cannabinoids, or dosage timing, may be expected to be useful for treating subjects experiencing insomnia.
- not all symptoms of insomnia may be effectively or equally treated by administering a subject with various formulations of cannabinoids.
- oral pulse-release compositions and dosage forms described herein may provide particular advantages as compared to other medications for treating sleep disorders.
- administering a subject in need of treatment for a sleep disorder with an oral pulse-release dosage form of the present disclosure may result in an increase in the subject's total sleeping time during the night.
- the administering may result in an increase in the subject's total light sleeping time during the night.
- the administering may result in an increase in the subject's light sleeping time as a proportion of total sleeping time during the night.
- the administering may result in an increase in the subject's total time in bed during the night.
- the effects of the administering on the subject may be measured using a SleepScore Max® system (e.g., see Example 4).
- the administering may result in an increase in SleepScore number as determined using a SleepScore Max® system.
- the administering may result in the subject experiencing an increase in feeling well rested in the morning and/or during the day, perceived sleep quality, perceived total sleep time during the night, sleep satisfaction, or any combinations thereof.
- the administering may result in the subject experiencing a decrease in perceived frequency of awakenings during the night, number of times out of bed at night, number of naps during the day, or perceived time awake at night, or any combinations thereof.
- the subject in need of treatment may be experiencing insomnia that is primarily characterized by an inability to stay asleep during the night.
- the insomnia may be characterized using objective measurements, e.g. using a SleepScore Max® system.
- characterization of the sleep disorder is reported by the subject, e.g. identified subjectively, or without using objective analysis e.g. using a SleepScore Max® system.
- the administering may not result in a decrease in latency to sleep onset, an alteration of time in deep sleep and/or REM sleep, a hangover effect during the day after the administering, or any combinations thereof.
- the administering may result in a decrease in latency to sleep onset.
- the subject may have been previously been administered with one or more cannabinoids for treating a medical condition.
- the subject may have previously used medical marijuana for one or more medical conditions.
- subject refers to a warm blooded animal such as a mammal which is treated for a condition that causes at least one symptom. It is understood that at least humans, dogs, cats, and horses are within the scope of the meaning of the term. In some embodiments, the subject is a human. In particular, the subject may be in need of treatment for a sleep disorder, e.g. insomnia.
- a sleep disorder e.g. insomnia
- treat or “treatment”, or a derivative thereof, contemplates partial or complete amelioration of at least one symptom associated with the condition of the subject.
- Example 1 Formulations of Example THC and CBN Oral Pulse-Release Dosage Forms
- This Example provides example formulations of a pulse-release THC and CBN oral dosage forms of the present disclosure.
- First pulse-release component THC 5 mg 5.4% CBN 2.5 mg 2.7% Microcrystalline Cellulose 65 mg 70.7% Hydroxypropylmethylcellulose 10 mg 10.8% Lactose 5 mg 5.4% Sodium starch glycolate 4 mg 4.3% Magnesium stearate 0.5 mg 0.5% Total 92.0 mg 100.0% Second pulse-release component THC 5 mg 3.0% CBN 2.5 mg 1.5% Microcrystalline Cellulose 120 mg 71.1% Methacrylic acid copolymer 40 mg 23.7% Magnesium stearate 0.7 mg 0.4% Colloidal silicone dioxide 0.5 mg 0.3% Total 168.7 mg 100.0%
- first pulse-release component that may be combined with any second pulse-release component described herein, e.g. may be combined with the second pulse-release component of Example 1(b) in some embodiments.
- first pulse-release component that may be combined with any second pulse-release component described herein, e.g. may be combined with the second pulse-release component of Example 1(b) in some embodiments.
- First pulse-release component THC 10.0 mg 5.3% CBN 5.0 mg 2.7% Microcrystalline Cellulose 125.0 mg 66.8% Hydroxypropylmethylcellulose 35.0 mg 18.7% Croscarmellose Sodium 11 mg 5.9% Magnesium stearate 1.2 mg 0.6% Total 187.2 mg 100.0% Second pulse-release component THC 5 mg 3.8% CBN 2.5 mg 1.9% Microcrystalline Cellulose 95 mg 71.4% Methacrylic acid copolymer 30 mg 22.6% Magnesium stearate 0.25 mg 0.2% Colloidal silicone dioxide 0.25 mg 0.2% Total 133.0 mg 100.0%
- First pulse-release component THC 10.0 mg 5.3% CBN 5.0 mg 2.7% Microcrystalline Cellulose 125.0 mg 66.8% Hydroxypropylmethylcellulose 35.0 mg 18.7% Croscarmellose Sodium 11 mg 5.9% Magnesium stearate 1.2 mg 0.6% Total 187.2 mg 100.0% Second pulse-release component THC 10 mg 3.6% CBN 5 mg 1.8% Microcrystalline Cellulose 200 mg 71.2% Methacrylic acid copolymer 65 mg 23.1% Magnesium stearate 0.5 mg 0.2% Colloidal silicone dioxide 0.5 mg 0.2% Total 281.0 mg 100.0%
- First pulse-release component THC 10.0 mg 5.3% CBN 5.0 mg 2.7% Microcrystalline Cellulose 125.0 mg 66.8% Hydroxypropylmethylcellulose 35.0 mg 18.7% Croscarmellose Sodium 11 mg 5.9% Magnesium stearate 1.2 mg 0.6% Total 187.2 mg 100.0% Second pulse-release component THC 20.0 mg 6.1% CBN 10.0 mg 3.0% Microcrystalline Cellulose 225.0 mg 68.3% Methacrylic acid copolymer 72.0 mg 21.9% Magnesium stearate 1.5 mg 0.5% Colloidal silicone dioxide 0.75 mg 0.2% Total 329.3 mg 100.0%
- First pulse-release component THC 5.0 mg 5.3% CBN 10.0 mg 2.7% Microcrystalline Cellulose 125.0 mg 66.8% Croscarmellose Sodium 11 mg 5.9% Magnesium stearate 1.2 mg 0.6% Total 187.2 mg 100.0% Second pulse-release component THC 5.0 mg 3.8% CBN 10.0 mg 1.9% Microcrystalline Cellulose 215.0 mg 71.4% Hydroxypropylmethylcellulose acetate 57.0 mg 22.6% Magnesium stearate 1.5 mg 0.2% Colloidal silicone dioxide 0.75 mg 0.2% Total 289.25 mg 100.0%
- First pulse-release component THC 10.0 mg 4.7% CBN 10.0 mg 4.7%
- Second pulse-release component THC 5.0 mg 2.7% CBN 10.0 mg 5.4%
- Methacrylic acid copolymer 43.0 mg 23.4%
- Colloidal silicone dioxide 0.3 mg 0.2% Total 183.9 mg 100.0%
- First pulse-release component THC 10.0 mg 4.7% CBN 10.0 mg 4.7% Microcrystalline Cellulose 135.0 mg 63.2% Hydroxypropylmethylcellulose 41.3 mg 19.3% Croscarmellose Sodium 16 mg 7.5% Magnesium stearate 1.2 mg 0.6% Total 213.5 mg 100.0% Second pulse-release component THC 5.0 mg 2.7% CBN 10.0 mg 5.4% Microcrystalline Cellulose 125.0 mg 70.0% Cellulose Acteate Pthalate 43.0 mg 23.4% Magnesium stearate 0.6 mg 0.3% Third pulse-release component THC 5.0 mg 2.7% CBN 10.0 mg 5.4% Microcrystalline Cellulose 125.0 mg 70.0% Methacrylic acid copolymer 43.0 mg 23.4% Magnesium stearate 0.6 mg 0.3%
- First pulse-release component THC 2.5 mg 1.3% CBN 1.25 mg 0.6%
- Second pulse-release component THC 2.5 mg 1.4% CBN 1.25 mg 0.7%
- Colloidal silicone dioxide 0.3 mg 0.2% Total 172.65 mg 100.0%
- First pulse-release component THC 0.5 mg 0.3% CBN 5.0 mg 2.5%
- Second pulse-release component THC 0.5 mg 0.3% CBN 5.0 mg 2.9%
- First pulse-release component THC 1.0 mg 0.5% CBN 10.0 mg 4.9% Microcrystalline Cellulose 135.0 mg 66.0% Hydroxypropylmethylcellulose 41.3 mg 20.2% Croscarmellose Sodium 16 mg 7.8% Magnesium stearate 1.2 mg 0.6% Total 204.5 mg 100.0% Second pulse-release component THC 1.0 mg 0.6% CBN 10.0 mg 5.6% Microcrystalline Cellulose 125.0 mg 69.5% Methacrylic acid copolymer 43.0 mg 23.9% Magnesium stearate 0.6 mg 0.3% Colloidal silicone dioxide 0.3 mg 0.2% Total 179.9 mg 100.0%
- First pulse-release component THC 2.0 mg 0.9% CBN 20.0 mg 9.3% Microcrystalline Cellulose 135.0 mg 62.6% Hydroxypropylmethylcellulose 41.3 mg 19.2% Croscarmellose Sodium 16 mg 7.4% Magnesium stearate 1.2 mg 0.6% Total 215.5 mg 100.0% Second pulse-release component THC 2.0 mg 1.0% CBN 20.0 mg 10.5% Microcrystalline Cellulose 125.0 mg 65.5% Methacrylic acid copolymer 43.0 mg 22.5% Magnesium stearate 0.6 mg 0.3% Colloidal silicone dioxide 0.3 mg 0.2% Total 190.9 mg 100.0%
- Example 2 Formulation of an Example Oral Pulsatile Dosage Form of THC and CBN
- Example THC and CBN oral dosage forms of Example 1 may in some embodiments be formulated according to the methods described in Example 2.
- the THC and CBN is formulated in a 50:50 ratio of immediate release (“IR THC+CBN”, for release in pulse 1): extended release (“ER THC+CBN”, for release in pulse 2).
- VIVACOAT Protect E into an appropriately sized container. Weigh 60 mL Ethanol into a suitably sized beaker equipped with a magnetic stir bar. Place beaker with Ethanol onto the magnetic stir plate and begin mixing vigorously without splashing. Slowly add the VIVACOAT Protect E to the Ethanol while stirring. Stir speed may be adjusted as needed.
- the example pulse-release oral dosage form was placed in 0.1 N HCl for two hours, with sampling time points at 1, 1.5 and 2 hours, followed by 8 hours in sodium phosphate buffer pH 6.8, at 37° C. ⁇ 0.5° C., with sampling at 3, 3.5, 4, 5, 6, 7, 8, 9 and 10 hours.
- THC concentration was measured using HPLC.
- FIG. 1 is a graph reporting the in vitro dissolution release rate (g/mL per timepoint) of THC versus time in hours of an example 2-pulse oral pharmaceutical composition tablet.
- the immediate release component (providing pulse 1) began to be dissolved immediately, resulting in a first time of peak release rate (PRR 1 ) after 1-2 hours.
- Dissolution of the delayed release component (pulse 2) provided a second time of peak release rate (PRR 2 ) after 3-4 hours.
- FIG. 2 is a graph reporting the dissolution profile of cumulative release of % total THC dose versus time in hours of the example 2-pulse oral pharmaceutical composition tablet. 50% of the total dose of the THC API was released after about 2 hours, and 90% of the total dose of THC API was released after about 5 hours.
- Cannabis as a sleep improvement solution has been receiving increased attention, in light of the current legalization of cannabis for medical use in 33 states and Washington D.C.
- the influence of delta-9 Tetrahydrocannabinol (THC) combined with cannabinol (CBN) on sleep is preliminary, but pre-clinical research indicates that CBN may prolong sleep and be particularly effective when combined with other cannabinoids (Yoshida et al., 1995; Russo, 2011).
- the aim of the study in this Example was to evaluate the impact of a combination of 10 mg THC and 5 mg CBN in a pulse-release tablet on the ability for participants (medical cannabis users) to stay asleep. The effect of the combination tablet was evaluated using objectively measured and self-reported data.
- SleepScore Max® (Consumer Sleep Solutions LLC, Delaware) was used to measure objective sleep, and self-report questionnaires were used to measure perceived sleep.
- the SleepScore Max® device uses Ultra-Wideband Technology to track the subject's bodily gross and micro movements. SleepScore Max®, is a validated non-contact monitor designed to unobtrusively and objectively measure sleep at the user's home.
- THC Delta-9 tetrahydrocannabinol
- Curio Wellness, LLC recruited medical cannabis patients, certified by the Maryland Medical Cannabis Commission, who self-identified as experiencing insomnia, in particular the subjects in this study felt they had trouble staying asleep. Eligible participants were asked to visit Curio Wellness dispensary in person on two occasions. During the second visit, they picked up the cannabis pulse-release dosage and reviewed the study instructions.
- the pre-product use period consisted of 3 weeks during which participants were instructed to track their sleep every night using SleepScore Max and complete a brief daily questionnaire each morning. During this period, participants had not yet received the test product.
- the product use period consisted of 3 weeks during which participants were asked to use the test product every night, track their sleep with SleepScore Max every night, and complete a brief daily questionnaire each morning. In addition to the brief daily questionnaires that were sent each morning, participants were asked to complete three more in-depth sleep experience questionnaires. The first of these sleep experience questionnaires was completed prior to product use, the second was completed after 1 week of product use, and the third was completed at the end of the study (after 3 weeks of product use).
- Each study tablet contained 15 mg of total cannabinoids (10 mg of THC+5 mg of CBN). These specific concentrations are commercially available to medical cannabis users in Maryland and were chosen for the current study based on previous research conducted by Curio Wellness. Tablets were a pulse-release dosage form as described in Example 1(a).
- SleepScore Max® provides standard annotated 30 second epoch sleep stage data and commonly used sleep metrics such as time to fall asleep (sleep onset latency), number of awakenings, start and end of sleep sessions, and total sleep time. Time spent in light sleep, deep sleep, and REM sleep (e.g. in minutes) together add up to total sleep time.
- Wake after sleep onset describes the total number of minutes a person is awake after falling asleep for the first time and before waking up prior to getting up.
- the total time in bed describes the time between getting in and out of bed (from “lights out, start tracking session” to “lights on, stop tracking session” according to the SleepScore Max® app). With these measures, sleep efficiency and sleep maintenance can be calculated. Sleep efficiency (in %) is calculated by dividing total sleep time by time in bed. Sleep efficiency of 85% and higher is considered to reflect good sleep quality (Ohayon et al., 2017). Sleep maintenance (in %) describes the ability of staying asleep once asleep, taking into account waking up too early (before getting out of bed) and/or struggling to get back to sleep (but not the time it takes to fall asleep initially) and is calculated by dividing total sleep time by the sum of the duration of all sleep stages, including wake, after initially falling asleep. Also, all four relative stage durations (% Light, % Deep, % REM, and % Wake) were calculated by dividing stage duration by the sum of the duration of all sleep stages, including wake, after initially falling asleep.
- SleepScore Max® provided three sleep scores: SleepScore®, Body Score, and Mind Score. These are normalized 100-point sleep quality scales, based on proprietary algorithms, using scientific averages for a user's age and gender (Ohayon et al., 2004). SleepScore® is defined by six sleep parameters (total sleep duration, time to fall asleep, time in light sleep, time in deep sleep, time in REM, and number of awakenings throughout the night) and can be regarded as a general sleep quality scale.
- Mind Score reflects the amount of REM sleep, which is known to play an important role in creative thinking, problem solving, and emotional processing.
- Body Score reflects the amount of deep sleep, which is considered restorative sleep and is linked to the perception of feeling well-rested the next day.
- Max R is a slimmed down version of the publicly available SleepScore Max® app, dedicated to serve as a sleep recording device, and available for researchers at request.
- Max R sleep recorder tracks sleep in the same way as the publicly available app, but it does not display sleep data and does not offer consumer features such as the sleep guide or smart alarm. It simply acts as a sleep tracker.
- Nightly objective sleep data and daily self-report data were analyzed in R (version 3.5.2) using multilevel regression analyses, taking into account the nested structure of the data (nights within subjects). An alpha level of 0.05 was used.
- MS Excel version 1901, for Windows was used to analyze the quantitative self-report sleep data from the sleep experience questionnaires. Descriptive statistics and one-tailed, paired-samples t-tests were conducted, using an alpha level of 0.05. Analyses compared responses to the sleep experience questionnaire administered before product use to the subsequent sleep experience questionnaires.
- the average age of study participants was 47, ranging from 22 to 69. The sample was 57% female. Over three-quarters (77%) described their race as White, and over half (54%) were married. The majority (57%) were working full-time, and 63% had finished college or earned graduate degrees. Annual household income ranged from less than $20,000 (3%) to $100,000 or higher (40%).
- each average was calculated by averaging nights across participants, and then averaging those participants' averages to a single simple average, listed under “Observed” in the Table 1.
- Observed a single simple average
- Estimated a single simple average
- Listed under “Estimated” in Table 1 are the outcomes of the multilevel regression analyses.
- Analyses of the daily self-report data suggested that the pulse-release dosage helped participants experience better sleep. Analyses of the daily self-report data suggested that the test product helped participants experience better sleep. Participants perceived fewer nighttime awakenings after falling asleep, going from 2.87 before product use to 2.33 during product use (p ⁇ 0.0001; 19% decrease). They also reported getting out of bed fewer times, from 1.21 before product use to 0.95 during product use (p ⁇ 0.0001; 21% decrease). In addition, participants reported a 22% improvement in feeling well-rested in the morning (p ⁇ 0.0001), with an average rating of 53.32 before product use and a rating of 65.21 during product use. Participants reported a 18% increase in overall sleep quality (p ⁇ 0.0001), going from an average of 57.36 before product use to 67.90 during product use. See Table 2.
- each average was calculated by averaging nights across participants, and then averaging those participants' averages to a single simple average, listed under “Observed” in Table 2.
- the results of the daily questionnaires were confirmed by significant sleep improvements that were observed when comparing the sleep experience questionnaires.
- the first of these sleep experience questionnaires was completed before the product use period, the second was completed after 1 week of product use, and the third was completed at the end of the study (after 3 weeks of product use).
- First, to test for a 1-week effect we compared participants' perceptions of their sleep after 1 week of using the product to how they perceived their sleep before using the product. Significant improvements were found for number of awakenings, time awake during the night after falling asleep, total sleep time, feeling well-rested in the morning, overall sleep satisfaction, and frequency of daytime napping.
- participants' perceptions of their sleep at the end of the study were compared to how they perceived their sleep before using the product.
- the validation study in this Example evaluated the effectiveness of a pulse-release oral dosage form product combining THC with CBN to improve ability to stay asleep.
- Medical cannabis patients certified by the Maryland Medical Cannabis Commission who felt they had trouble staying asleep were recruited by Curio Wellness into the study.
- the research participants tracked their sleep for 3 weeks and then tested the product for 3 weeks in their own homes while continuing to track their sleep. This way of testing has the advantage of providing insight into the effectiveness of the product under real-life conditions and hence yielding more ecologically valid results.
- the tablets were administered as a pulse-release dosage form: the dosage form was designed so that half of the dosage was released immediately after oral administration, and the remaining half was released 2-3 hours later.
- the study in this Example found that an example product combining THC with CBN was directly associated with both improved objective and perceived sleep quality and duration in a sample of medical cannabis users.
- This Example describes a study evaluating the impact of a combination of 10 mg THC and 5 mg CBN in an immediate-release sublingual tablet on the ability for participants (medical cannabis users) to fall asleep.
- the effect of the combination tablet was evaluated using objectively measured and self-reported data.
- the combination cannabinoid tablet was tested in 28 medical cannabis patients certified by the Maryland Medical Cannabis Commission who felt they had trouble falling asleep, covering 445 nights of use of the product.
- the self-report data did not show improvement in how many minutes participants felt it took them to fall asleep. Perceived sleep onset did not change significantly across the daily questionnaires or the three sleep experience questionnaires. However, there was significant improvement in how often participants felt that they fell asleep within their preferred amount of time, going from an average of 3 nights per week to 4 nights per week.
- Curio Wellness recruited medical cannabis patients, certified by the Maryland Medical Cannabis Commission, who self-identified as experiencing insomnia, in particular the subjects in this study felt they had trouble falling asleep. Curio Wellness obtained informed consent from all participants and provided them with the cannabis test product, a SleepScore Max® device, a guide for using the research version of the SleepScore Max® companion app, and additional study instructions.
- the medical cannabis patients had to be at least 21 years old and willing to track their sleep every night for 6 weeks. They also had to be willing to use the test product every night for 3 weeks, and willing to discontinue other cannabis use at least 3 hours before bed during the product use period.
- sleep disorders e.g., narcolepsy, restless leg syndrome, sleep apnea
- psychological disorders affecting sleep e.g., clinical depression, bipolar disorder, schizophrenia
- sleep medications prescription or over-the-counter
- anti-convulsant medications were excluded, as were people who typically had 3 or more alcoholic beverages on 4 or more nights per week.
- Women who were pregnant, lactating, or planning to become pregnant in the next 2 months were excluded.
- Other exclusion criteria included being a shift worker, having a child at home under 12 months old, or planning to travel across multiple time zones or be away from home for more than 5 days during the entire study.
- the pre-product use period consisted of 3 weeks during which participants were instructed to track their sleep every night using SleepScore Max® and complete a brief daily questionnaire each morning. During this period, participants had not yet received the test product.
- the product use period consisted of 3 weeks during which participants were asked to use the test product every night, track their sleep with SleepScore Max® sleep measurement system every night, and complete a brief daily questionnaire each morning.
- Each tablet contained 15 mg of total cannabinoids (10 mg of THC+5 mg of CBN). These specific concentrations are commercially available to medical cannabis users in Maryland and were chosen for the current study based on previous research conducted by Curio Wellness.
- the tablet form was dissolvable immediate release, and the delivery method was sublingual.
- the objective sleep analyses included 28 participants.
- the perceived sleep analyses included self-report data from 26 participants.
- the average age was 41, ranging from 24 to 71. Based on data collected in the first sleep experience questionnaire, 65% were female, 84% described their race as White, and over half (54%) were married. The majority (53%) were working full-time, and 43% had finished college or earned graduate degrees. Annual household income ranged from less than $20,000 (4%) to $100,000 or higher (34%).
- the results of the daily questionnaires were confirmed by significant sleep improvements that were observed when comparing the sleep experience questionnaires.
- the first of these sleep experience questionnaires was completed before the product use period, the second was completed after 1 week of product use, and the third was completed at the end of the study (after 3 weeks of product use).
- This validation study evaluated the effectiveness of a product combining THC with CBN to help with falling asleep. Medical cannabis patients certified by the Maryland Medical Cannabis Commission who felt they had trouble falling asleep were recruited by Curio Wellness into the study. The research participants tracked their sleep for 3 weeks and then tested the product for 3 weeks in their own homes while continuing to track their sleep. This way of testing has the advantage of providing insight into the effectiveness of the product under real-life conditions and hence yielding more ecologically valid results.
- SleepScore Max® was used to measure objective sleep, and self-report questionnaires were used to measure perceived sleep. In addition to brief daily questionnaires that were sent each morning of the study to measure compliance and sleep experiences, participants completed 3 longer surveys assessing perceived sleep and user experiences.
- test product was unexpectedly associated with a statistically significant increase in how long it took to fall asleep. Participants' average onset time rose from 24 minutes before product use to 26 minutes during product use. The objective data also revealed that taking longer to fall asleep impacted sleep efficiency, meaning that participants spent less time asleep while they were in bed. Also, their ability to stay asleep was slightly negatively affected, as indicated by a decrease in sleep maintenance.
- the self-report data did not show statistically significant improvement in how many minutes participants felt it took them to fall asleep. Perceived sleep onset did not change significantly across the daily questionnaires or the three sleep experience questionnaires. However, at the end of the study there was significant improvement in how often participants felt that they fell asleep within their preferred amount of time, going from an average of 3 nights per week to 4 nights per week.
- the term “and/or” as used in a phrase such as “A, B, and/or C” is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).
- the term “about” refers to a value or composition that is within an acceptable error range for the particular value or composition as determined by one of ordinary skill in the art, which will depend in part on how the value or composition is measured or determined, i.e., the limitations of the measurement system.
- “about” or “approximately” can mean within one or more than one standard deviation per the practice in the art.
- “about” or “approximately” can mean a range of up to 10% (i.e., ⁇ 10%) or more depending on the limitations of the measurement system.
- about 5 mg can include any number between 4.5 mg and 5.5 mg.
- administering refers to the physical introduction of an agent to a subject, using any of the various methods and delivery systems known to those skilled in the art.
- routes of administration include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral routes of administration, for example by injection or infusion.
- parenteral administration means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion, as well as in vivo electroporation.
- Non-parenteral routes include oral, topical, epidermal or mucosal route of administration, for example, intranasally, vaginally, rectally, sublingually or topically.
- Administering can also be performed, for example, once, a plurality of times, and/or over one or more extended periods.
- the above disclosure contains various examples of oral pulse-release compositions and dosage forms, and methods of treating sleep disorders in a subject by administering the oral pulse-release compositions and dosage forms. Aspects of these various examples may all be combined with one another, even if not expressly combined in the present disclosure, unless they are clearly mutually exclusive.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Inorganic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Nutrition Science (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Physiology (AREA)
- Anesthesiology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines Containing Plant Substances (AREA)
Abstract
Description
- This application claims the benefit of U.S. Provisional Application 63/143,320 filed Jan. 29, 2021, the contents of which are herein incorporated by reference in their entirety.
- The present disclosure relates to oral cannabinoid pharmaceutical compositions and methods of treating sleep disorders using the oral cannabinoid pharmaceutical compositions.
- The Centers for Disease Control and Prevention have declared insufficient sleep a public health problem. It is recommended that adults get at least 7 hours of sleep per night for optimal health and wellbeing (Watson et al., Sleep. 2015 Aug. 1; 38(8):1161-83). However, one-third of US adults report getting less than 7 hours of sleep per night and up to 70 million suffer from sleep disorders (Liu Y et al., Morb Mortal Wkly Rep. 2016 Feb. 19; 65(6):137-41; National Heart, Lung, and Blood Institute, National Sleep Disorders Research Plan, 2003. Bethesda, Md.: National Institutes of Health; 2003). Insufficient sleep is associated with a plethora of adverse health conditions including diabetes, hypertension, heart disease, stroke, depression, obesity, impaired immune function and increased risk of death (Watson et al., Sleep. 2015 Aug. 1; 38(8):1161-83). Existing sleep aids can often be ineffective or only marginally effective, and some may have a profound deleterious impact on quality of sleep, in particular on REM sleep and deep sleep components of the sleep experience. However, development of improved sleep medications is challenging.
- According to a first aspect, the present disclosure relates provides an oral pulse-release dosage form, comprising a total daily dose of a first cannabinoid active pharmaceutical ingredient (API1) and a total daily dose of a second cannabinoid API (API2). The oral pulse-release dosage form comprises a first pulse-release component (C1) comprising a first portion (P1) of the first cannabinoid API (API1P1) and a first portion (P1) of the second cannabinoid API (API2P1). The oral pulse-release dosage form also comprises at least a second pulse-release component (C2) comprising a second portion (P2) of the first cannabinoid API (API1P2) and a second portion (P2) of the second cannabinoid API (API2P2). The total daily dose of each of the API1 and the API2 is divided between the first portion (P1) in the first pulse-release component (C1) and at least the second portion (P2) in the at least second pulse-release component (C2). When the pulse-release dosage form is placed in an aqueous solution of 0.1N HCl pH 1.1 for 2 hours followed by 8 hours in sodium phosphate buffer at pH 6.8, at 37° C.±0.5° C., the pulse-release dosage form provides release of the API1P2 and the API2P2 beginning from 2 to 6 hours after release of the API1P1 and the API2P1 begins.
- The oral pulse-release dosage form may include the following details, which can be combined with one another in any combinations unless clearly mutually exclusive:
- The pulse-release dosage form may provide a second time of peak release rate (PRR2) of each of the API1 (PRR2API1) and the API2 (PRR2API2) from about 2 to 6 hours after a first time of PRR (PRR1).
- The PRR1 may be after 1-2 hours.
- The first cannabinoid API1 may be delta-9-tetrahydrocannabinol (THC) and the second cannabinoid API2 may be cannabinol (CBN). The total daily dose of the THC may be from 1 mg to 40 mg and the total daily dose of the CBN may be from 2.5 mg to 100 mg.
- The first cannabinoid API1 may be THC and the second cannabinoid API2 may be CBN. The total daily dose of the THC may be selected from: at least 1 mg, at least 2 mg, at least 3 mg, at least 4 mg, at least 5 mg, at least 6 mg, at least 8 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, and at least 35 mg, and the total daily dose of the CBN may be selected from: at least 2.5 mg, at least 3 mg, at least 4 mg, at least 5 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, and at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, and at least 95 mg.
- The first pulse-release component (C1) may be an immediate release (IR) formulation of the first cannabinoid API1 and the second cannabinoid API2, comprising: the first portion (P1) of the first cannabinoid API (API1P1) and a first portion (P1) of the second cannabinoid API (API2P1), and one or more binders, one or more disintegrants, one or more lubricants, one or more flow aids, or any combinations thereof. The second pulse-release component (C2) may be a delayed release (DR) formulation of the first cannabinoid API1 and the second cannabinoid API2, comprising: the second portion (P2) of the first cannabinoid API (API1P2) and a second portion (P2) of the second cannabinoid API (API2P2), and one or more binders, one or more lubricants, one or more flow aids, or any combinations thereof. The second pulse-release component may be coated with a delayed-release layer comprising one or more pH-dependent and/or non-pH-dependent polymers, and optionally one or more plasticizers, one or more pore formers, or one or lubricants, or any combinations thereof.
- For each API, the first portion (P1) may be independently selected from 25% to 75% of the total daily dose, and for each API the second portion (P2) may be independently selected from 25% to 75% of the total daily dose.
- In the first pulse-release component (C1), the second pulse-release component (C2), or both, when present: the binders may comprise from 1 to 60% (w/w), the disintegrants may comprise from 0.05 to 15% (w/w), the lubricants may comprise from 0.5 to 5% (w/w), the flow aids may comprise from 0.05 to 0.5% (w/w), and the pH-dependent and/or non-pH-dependent polymers may comprise from 0.5 to 35% (w/w).
- The first pulse-release component (C1) may comprise from 0.5 mg to 30 mg of the first cannabinoid active pharmaceutical ingredient (API1), wherein the API1 is THC, and from 1.25 mg to 75 mg of the second cannabinoid active pharmaceutical ingredient (API1), wherein the API1 is CBN. The first pulse-release component (C1) may comprise microcrystalline cellulose, hydroxypropylmethylcellulose, and magnesium stearate. The second pulse-release component (C2) may comprise from 0.5 mg to 30 mg of the first cannabinoid active pharmaceutical ingredient (API1), wherein the API1 is THC, and from 1.25 mg to 75 mg of the second cannabinoid active pharmaceutical ingredient (API1), wherein the API1 is CBN. The second pulse-release component (C2) may comprise microcrystalline cellulose, methacrylic acid copolymer, magnesium stearate, and colloidal silicone dioxide.
- According to a second aspect, the present disclosure relates provides an oral pulse-release dosage form, comprising a total daily dose of a first cannabinoid active pharmaceutical ingredient (API1) and a total daily dose of a second cannabinoid API (API2). The pulse-release dosage form comprises a first pulse-release component (C1) comprising a first portion (P1) of the first cannabinoid API (API1P1) and a first portion (P1) of the second cannabinoid API (API2P1), a second pulse-release component (C2) comprising a second portion (P2) of the first cannabinoid API (API1P2) and a second portion (P2) of the second cannabinoid API (API2P2), and at least a third pulse-release component (C3) comprising a third portion (P3) of the first cannabinoid API (API1P3) and a third portion (P3) of the second cannabinoid API (API2P2). The total daily dose of each of the API1 and the API2 may be divided between the first portion (P1) in the first pulse-release component (C1), the second portion (P2) in the second pulse-release component (C2), and at least the third portion (P3) in the at least third pulse-release component (C3). When the pulse-release dosage form is placed in an aqueous solution of 0.1N HCl pH 1.1 for 2 hours followed by 8 hours in sodium phosphate buffer at pH 6.8, at 37° C.±0.5° C., the pulse-release dosage form provides release of the API1P2 and the API2P2 beginning from 1 to 4 hours after release of the API1P1 and the API2P1 begins, and release of the API1P3 and the API2P3 beginning from 1 to 4 hours after release of the API1P2 and the API2P2 begins.
- The oral pulse-release dosage form may include the following details, which can be combined with one another in any combinations unless clearly mutually exclusive:
- The pulse-release dosage form may provide a second time of peak release rate (PRR2) of each of the API1 (PRR2API1) and the API2 (PRR2API2) from about 1 to 4 hours after a first time of PRR (PRR1) and a third time of peak release rate (PRR3) of each of the API1 (PRR3API1) and the API2 (PRR3API2) from about 1 to 4 hours after the second time of PRR (PRR2).
- The PRR1 may be after 1-2 hours.
- The first cannabinoid API1 may be delta-9-tetrahydrocannabinol (THC) and the second cannabinoid API2 may be cannabinol (CBN). The total daily dose of the THC may be from 10 mg to 40 mg and the total daily dose of the CBN may be from 5 mg to 100 mg.
- The first cannabinoid API1 may be THC and the second cannabinoid API2 may be CBN, and the total daily dose of the THC may be selected from: at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, and at least 35 mg, and the total daily dose of the CBN may be selected from: at least 5 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, and at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, and at least 95 mg.
- The first pulse-release component (C1) may be an immediate release (IR) formulation of the first cannabinoid API1 and the second cannabinoid API2, comprising the first portion (P1) of the first cannabinoid API (API1P1) and a first portion (P1) of the second cannabinoid API (API2P1). The first pulse-release component (C1) may comprise one or more binders, one or more disintegrants, one or more lubricants, one or more flow aids, or any combinations thereof. The second pulse-release component (C2) may be a delayed release (DR) formulation of the first cannabinoid API1 and the second cannabinoid API2, comprising the second portion (P2) of the first cannabinoid API (API1P2) and a second portion (P2) of the second cannabinoid API (API2P2). The second pulse-release component (C2) may comprise one or more binders, one or more lubricants, one or more flow aids, or any combinations thereof. The second pulse-release component may be coated with a first delayed-release layer comprising one or more pH-dependent and/or non-pH-dependent polymers, and optionally one or more plasticizers, one or more pore formers, one or lubricants, or any combinations thereof. The third pulse-release component (C3) may be a delayed release (DR) formulation of the first cannabinoid API1 and the second cannabinoid API2, comprising the third portion (P3) of the first cannabinoid API (API1P3) and a third portion (P3) of the second cannabinoid API (API2P3). The third pulse-release component (C3) may comprise one or more binders, one or more lubricants, one or more flow aids, or any combinations thereof. The third pulse-release component may be coated with a second delayed-release layer comprising one or more pH-dependent and/or non-pH-dependent polymers, and optionally one or more plasticizers, one or more pore formers, one or lubricants, or any combinations thereof.
- For each API, the first portion (P1) may be independently selected from 25% to 75% of the total daily dose, for each API, the second portion (P2) may be independently selected from 25% to 75% of the total daily dose, and, for each API, the third portion (P3) may be independently selected from 25% to 75% of the total daily dose.
- In the first pulse-release component (C1), the second pulse-release component (C2), and/or the third pulse-release component (C3), when present: the binders may comprise from 1 to 60% (w/w), the disintegrants may comprise from 0.05 to 15% (w/w), the lubricants may comprise from 0.5 to 5% (w/w), the flow aids may comprise from 0.05 to 0.5% (w/w), and the pH-dependent and/or non-pH-dependent polymers may comprise from 0.5 to 35% (w/w).
- The first pulse-release component (C1) may comprise from 2.5 mg to 30 mg of the first cannabinoid active pharmaceutical ingredient (API1), wherein the API1 is THC, and from 1.25
mg 30 to 75 mg of the second cannabinoid active pharmaceutical ingredient (API1), wherein the API1 is CBN. The first pulse-release component (C1) may comprise microcrystalline cellulose, hydroxypropylmethylcellulose, croscormellose sodium, magnesium stearate, or any combinations thereof. The second pulse-release component (C2) may comprise from 2.5 mg to 30 mg of the first cannabinoid active pharmaceutical ingredient (API1), wherein the API1 is THC, and from 1.25 mg to 75 mg of the second cannabinoid active pharmaceutical ingredient (API1), wherein the API1 is CBN. The second pulse-release component (C2) may comprise microcrystalline cellulose, cellulose acetate phthalate, magnesium stearate, or any combinations thereof. The third pulse-release component (C3) may comprise from 2.5 mg to 30 mg of the first cannabinoid active pharmaceutical ingredient (API1), wherein the API1 is THC, and from 1.25 mg to 75 mg of the second cannabinoid active pharmaceutical ingredient (API1), wherein the API1 is CBN. The third pulse-release component (C3) may comprise microcrystalline cellulose, methacrylic acid copolymer, magnesium stearate, or any combinations thereof. - According to a third aspect, the present disclosure provides a method of treating a sleep disorder in a subject in need thereof, the method comprising: administering to the subject an oral pulse-release dosage form described herein.
- The method may include the following details, which can be combined with one another in any combinations unless clearly mutually exclusive:
- The administering may result in an increase in the subject's total sleeping time during the night.
- The administering may result in an increase in the subject's total light sleeping time during the night.
- The administering may result in an increase in the subject's light sleeping time as a proportion of total sleeping time during the night.
- The administering may result in an increase in the subject's total time in bed during the night.
- The increase may be measured using a SleepScore Max® system.
- The administering may result in an increase in SleepScore number as determined using a SleepScore Max® system.
- The administering may result in the subject experiencing an increase in one or more of: feeling well rested in the morning and/or during the day, perceived sleep quality, perceived total sleep time during the night, or sleep satisfaction. Additionally or alternatively, the subject may experience a decrease in one or more of: perceived frequency of awakenings during the night, number of times out of bed at night, number of naps during the day, or perceived time awake at night.
- The sleep disorder may comprise insomnia, wherein the insomnia is primarily characterized by an inability to stay asleep during the night.
- The insomnia may be characterized using a SleepScore Max® system.
- Characterization of the sleep disorder may be reported by the subject.
- The administering may not result in a decrease in latency to sleep onset, an alteration of time in deep sleep and/or REM sleep, a hangover effect during the day after the administering, or any combinations thereof.
- The subject may have previously been administered with one or more cannabinoids for treating a medical condition.
- The administering may be up to 30 minutes, 1 hour, or 2 hours before the subject intends to begin sleeping at night.
- The present disclosure may be further understood through reference to the attached figures in combination with the detailed description that follows.
-
FIG. 1 is a graph reporting an example in vitro dissolution release rate (g/mL per timepoint) of delta-9 Tetrahydrocannabinol (THC) versus time in hours of an example 2-pulse oral pharmaceutical composition tablet. -
FIG. 2 is a graph reporting an example dissolution profile of cumulative release of % total THC dose versus time in hours of an example 2-pulse oral pharmaceutical composition tablet. -
FIG. 3 is a schematic showing an example clinical study timeline. -
FIG. 4 is a graph reporting example medical conditions for which cannabis was used. Up to 3 conditions could be selected by each participant. -
FIG. 5 is a graph reporting example sleep concerns of clinical trial participants prior to using an example pulse-release dosage form of the present disclosure. Percentages do not total 100 because multiple answers were allowed. -
FIG. 6 is a graph reporting example forms of cannabis being used by clinical trial participants to help with sleep prior to the product use period. Percentages do not total 100 because multiple answers were allowed. -
FIG. 7 is a graph reporting example data on self-reported average number of times participants woke up per night. -
FIG. 8 is a graph reporting example self-reported average amount of time per night spent awake after initially falling asleep. -
FIG. 9 is a graph reporting example self-reported average number of hours and minutes slept per night. -
FIG. 10 is a graph reporting example self-reported number of mornings per week participants woke up feeling well rested. -
FIG. 11 is a graph reporting example self-reported number of nights per week participants felt satisfied with their sleep. -
FIG. 12 is a graph reporting example self-reported number of days per week participants napped. -
FIG. 13 is a schematic showing an example clinical study timeline. -
FIG. 14 is a graph reporting example medical conditions for which cannabis was used. Up to 3 conditions could be selected by each participant. -
FIG. 15 is a graph reporting example sleep concerns of clinical trial participants prior to using an example pulse-release dosage form of the present disclosure. Percentages do not total 100 because multiple answers were allowed. -
FIG. 16 is a graph reporting example forms of cannabis being used by clinical trial participants to help with sleep prior to the product use period. Percentages do not total 100 because multiple answers were allowed. -
FIG. 17 is a graph reporting example data on self-reported average number of days per week participants felt so sleepy/tired that it affected them at school/work or in their private life. Note: * indicates significant at p<0.05 after 1 week of use. ** indicates significant at p<0.05 after 3 weeks of use. -
FIG. 18 is a graph reporting example data on self-reported average sleepiness of participants at bedtime. Note: ** indicates significant at p<0.05 after 3 weeks of use. -
FIG. 19 is a graph reporting example data on self-reported average number of nights per week participants reported falling asleep in the amount of time that they preferred. Note: ** indicates significant at p<0.05 after 3 weeks of use. -
FIG. 20 is a graph reporting example data on self-reported average number of minutes it took to fall asleep per night. -
FIG. 21 is a graph reporting example data on self-reported average number of mornings per week participants woke up feeling well rested. Note: ** indicates significant at p<0.05 after 3 weeks of use. -
FIG. 22 is a graph reporting example data on self-reported average number of nights per week participants felt satisfied with their sleep. Note: ** indicates significant at p<0.05 after 3 weeks of use. - Insomnia, defined as difficulty falling asleep or staying asleep, is the most common sleep disorder with approximately 30% of adults having symptoms each year (National Sleep Foundation. What is Insomnia? https://www.sleepfoundation.org/insomnia/what-insomnia, Accessed 2019; The American Academy of Sleep Medicine. Insomnia. https://aasm.org/resources/factsheets/insomnia.pdf, Accessed 2019). It is a major contributing factor to motor vehicle deaths, and loss of productivity, due to insomnia, costs the US workforce $63.2 billion annually (The American Academy of Sleep Medicine. Insomnia. https://aasm.org/resources/factsheets/insomnia.pdf, Accessed 2019; Laugsand L E, Strand L B, Vatten L J, et. al. Insomnia Symptoms and Risk for Unintentional Fatal Injuries—The HUNT Study. Sleep. 2014 Nov. 1; 37(11):1777-86; Kessler R C, Berglund P A, Coulouvrat C, et al. Insomnia and the performance of US workers: results from the America insomnia survey. Sleep. 2011 Sep. 1; 34(9):1161-71). A number of sleep medications are available to improve sleep quality including prescription drugs, over-the-counter medication and alternative treatments. Of the alternative solutions available, cannabis has received increased attention over the last two decades with the legalization of medical cannabis in 33 states and Washington D.C. (National conference of state legislatures, State Medical Marijuana Laws. http://www.ncsl.org/research/health/state-medical-marijuana-laws.aspx, Accessed 2019). According to recent studies, two-thirds of medical cannabis users have reduced their sleep medication use since starting medical cannabis, and they expect medical cannabis to improve their sleep quality (Piper B J, DeKeuster R M, Beals M L, et al. Substitution of medical cannabis for pharmaceutical agents for pain, anxiety and sleep. J Psychopharmacol. 2017 May; 31(5):569-575; Altman B R, Mian M N, Slavin M, Earleywine M. Cannabis Expectancies for Sleep. J Psychoactive Drugs. 2019 Jul. 18:1-8). To date, the impact of cannabinoids on sleep is unclear.
- Delta-9 Tetrahydrocannabinol (THC) is one of the most widely studied cannabinoids on sleep, yet its effects are not well understood (Babson K A, Sottile J, Morabito D. Cannabis, Cannabinoids, and Sleep: A Review of the Literature. Curr Psychiatry Rep. 2017 April; 19(4):23; Gates P J, Albertella L, Copeland J. The effects of cannabinoid administration on sleep: a systematic review of human studies. Sleep Med Rev. 2014 December; 18(6):477-87). Early studies focused on the connection between THC and polysomnography. Cousens and DiMascio showed that THC significantly decreased time to fall asleep yet it causes a hangover effect, defined as continued effects of a cannabinoid drug felt by the subject during the following day (Cousens K, DiMascio A. (−)
Delta 9 THC as a hypnotic. An experimental study of three dose levels. Psychopharmacologia. 1973 Dec. 20; 33(4):355-64). Conversely, Chait reported that THC is not associated with a hangover effect (Chait L D. Subjective and behavioral effects of marijuana the morning after smoking. Psychopharmacology (Berl). 1990; 100(3):328-33). Other polysomnography studies suggested that THC reduces the duration of REM sleep and may increase the duration ofStage 4 sleep (Feinberg I, Jones R, Walker J M, et al. Effects of high dosage delta-9-tetrahydrocannabinol on sleep patterns in man. Clin Pharmacol Ther. 1975 April; 17(4):458-66; Pivik R T, Zarcone V, Dement W C, Hollister L E. Delta-9- tetrahydrocannabinol and synhexl: effects on human sleep patterns. Clin Pharmacol Ther. 1972 May-June; 13(3):426-35). Recent studies focusing on self-reported sleep quality are also inconsistent. A few studies have shown that THC is sedative and reduces sleep onset latency while many have found an association between THC and poor sleep quality (Nicholson A N, Turner C, Stone B M, Robson P J. Effect ofdelta 9 THC and Cannabidiol on Nocturnal Sleep and Early-morning Behavior in Young Adults. J Clin Psychopharmacol. 2004 June; 24(3):305-13; Tringale R, Jensen C. Cannabis and insomnia. Depression. 2011; 4(12):0-68; Ogeil R P, Phillips J G, Rajaratnam S M, Broadbear J H. Risky drug use and effects on sleep quality and daytime sleepiness. Hum Psychopharmacol. 2015 September; 30(5):356-63). Ultimately, in previous studies, the optimal THC concentration, route of administration and administration time needed to positively impact sleep quality has not been determined (Watson N F, Badr M S, Belenky G, et al.; Consensus Conference Panel. Joint consensus statement of the American Academy of Sleep Medicine and Sleep Research Society on the recommended amount of sleep for a healthy adult: methodology and discussion. Sleep. 2015 Aug. 1; 38(8):1161-83). - The present disclosure relates to oral cannabinoid pharmaceutical compositions and methods of treating sleep disorders using the oral cannabinoid pharmaceutical compositions.
- In some embodiments, an API of the present disclosure can be a cannabinoid. The term “cannabinoid” as used herein refers to several classes of compounds that can be found in plants of the genus Cannabis. There are at least 144 different cannabinoids that have been isolated from cannabis, exhibiting varied effects. Synthetic encompass a variety of distinct chemical classes: the classical cannabinoids structurally related to THC, the nonclassical cannabinoids (cannabimimetics) including the aminoalkylindoles, 1,5-diarylpyrazoles, quinolines, and arylsulfonamides as well as eicosanoids related to endocannabinoids.
- The classical cannabinoids are concentrated in a viscous resin of cannabis plants produced in structures known as glandular trichomes. The main classes of cannabinoids include, without limitation, THC (tetrahydrocannabinol), THCA (tetrahydrocannabinolic acid), CBD (cannabidiol), CBDA (cannabidiolic acid), CBN (cannabinol), CBG (cannabigerol), CBC (cannabichromene), CBL (cannabicyclol), CBV (cannabivarin), THCC (tetrahydrocannabiorcol), THCV (tetrahydrocannabivarin), THCP (tetrahydrocannabiphorol), CBDV (cannabidivarin), CBCV (cannabichromevarin), CBGV (cannabigerovarin), CBGM (cannabigerol monomethyl ether), CBE (cannabielsoin), and CBT (cannabicitran). Cannabinoids of the present disclosure include, without limitation: Cannabigerol-type (CBG) cannabinoids, such as Cannabigerol monomethyl ether, Cannabinerolic acid A, Cannabigerovarin, Cannabigerolic acid A, Cannabigerolic acid A monomethyl ether, and Cannabigerovarinic acid A; Cannabichromene-type (CBC) cannabinoids, such as (±)-Cannabichromene, (±)-Cannabichromenic acid A, (±)-Cannabivarichromene, (±)-Cannabichromevarin, and (±)-Cannabichromevarinic acid A; Cannabidiol-type (CBD) cannabinoids, such as (−)-Cannabidiol, Cannabidiol momomethyl ether, Cannabidiol-C4, (−)-Cannabidivarin, Cannabidiorcol, Cannabidiolic acid, and Cannabidivarinic acid; Cannabinodiol-type (CBND) cannabinoids, such as Cannabinodiol and Cannabinodivarin; Tetrahydrocannabinol-type (THC) cannabinoids, such as Δ9-Tetrahydrocannabinol, Δ9-Tetrahydrocannabinol-C4, Δ9-Tetrahydrocannabivarin, Δ9-Tetrahydrocannabiorcol, Δ9-Tetrahydro-cannabinolic acid A, Δ9-Tetrahydro-cannabinolic acid B, Δ9-Tetrahydro-cannabinolic acid-C4 A and/or B, Δ9-Tetrahydro-cannabivarinic acid A, Δ9-Tetrahydro-cannabiorcolic acid A and/or B, (−)-Δ8-trans-(6aR,10aR)-Δ8-Tetrahydrocannabinol, (−)-Δ8-trans-(6aR,10aR)-Tetrahydrocannabinolic acid A, and (−)-(6aS,10aR)-Δ9-Tetrahydrocannabinol; Cannabinol-type (CBN) cannabinoids, such as Cannabinol, Cannabinol-C4, Cannabivarin, Cannabinol-C2, Cannabiorcol, Cannabinolic acid A, and Cannabinol methyl ether; Cannabitriol-type (CBT) cannabinoids, such as (−)-(9R,10R)-trans-Cannabitriol, (+)-(9S,10S)-Cannabitriol, (±)-(9R,10S/9S,10R)-Cannabitriol, (−)-(9R,10R)-trans-10-O-Ethyl-cannabitriol, (±)-(9R,10R/9S,10S)-Cannabitriol-C3, 8,9-Dihydroxy-Δ6a(10a)-tetrahydrocannabinol, Cannabidiolic acid A cannabitriol ester, (−)-(6aR,9S,10S,10aR)-9,10-Dihydroxy-hexahydrocannabinol, Cannabiripsol, (−)-6a,7,10a-Trihydroxy-Δ9-tetrahydrocannabinol, 10-Oxo-Δ6a(10a)-tetrahydrocannabinol; Cannabielsoin-type (CBE) cannabinoids such as (5aS,6S,9R,9aR)-Cannabielsoin, (5aS,6S,9R,9aR)-C3-Cannabielsoin, (5aS,6S,9R,9aR)-Cannabielsoic acid A, (5aS,6S,9R,9aR)-Cannabielsoic acid B, (5aS,6S,9R,9aR)-C3-Cannabielsoic acid B, Cannabiglendol-C3, Dehydrocannabifuran, and Cannabifuran; Isocannabinoids such as (−)-Δ7-trans-(1R,3R,6R)-Isotetrahydrocannabinol, (±)-Δ7-1,2-cis-(1R,3R,6S/1S,3S,6R)-Isotetrahydro-cannabivarin, and (−)-Δ7-trans-(1R,3R,6R)-Isotetrahydrocannabivarin; Cannabicyclol-type (CBL) cannabinoids such as (±)-(1aS,3aR,8bR,8cR)-Cannabicyclol, (±)-(1aS,3aR,8bR,8cR)-Cannabicyclolic acid A, and (±)-(1aS,3aR,8bR,8cR)-Cannabicyclovarin; Cannabicitran-type (CBT) cannabinoids such as Cannabicitran; and Cannabichromanone-type (CBCN) cannabinoids such as Cannabichromanone, Cannabichromanone-C3, and Cannabicoumaronone.
- In some embodiments, the term “cannabinoid” as used herein refers to compounds that may be extracted from, and/or derived from Cannabis plants using methods known in the art. For example, cannabinoids can be separated from the cannabis plant by extraction with organic solvents or using supercritical solvent extraction with carbon dioxide. Cannabinoids may be obtained in oils extracted from cannabis plants, and thereafter further isolated, purified, and converted into derivatives. In some embodiments, the term “cannabinoid” as used herein may also refer to such compounds that may be produced synthetically or using recombinant biotechnology methods, as may be identified by persons of ordinary skill in the art.
- Cannabinoids of the present disclosure may include stereoisomers thereof, and modified forms thereof, such as a pharmaceutically acceptable salt, ester, derivative, analog, prodrug, hydrate, or solvate thereof.
- In some embodiments, a pharmaceutical compositions of the present disclosure can include, without limitation, one or more cannabinoids, two or more cannabinoids, or three or more cannabinoids. In some embodiments, the cannabinoid may be THC, CBN, CBD, or any combinations thereof.
- The best studied cannabinoids include tetrahydrocannabinol (THC), cannabidiol (CBD) and cannabinol (CBN). Δ9- tetrahydrocannabinol (Δ9-THC or THC), is also known by its International Non-Proprietary Name (INN) as dronabinol. The unsaturated bond in the cyclohexene ring is located between C-9 and C-10 in the more common dibenzopyran ring numbering system. There are four stereoisomers of THC, but only the (−)-trans isomer occurs naturally (CAS-1972-08-03). The fully systematic name for this THC isomer is (−)-(6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol. Two related substances, Δ9- tetrahydrocannabinol-2-oic acid and Δ9-tetrahydrocannabinol-4-oic acid (THCA), are also present in cannabis, sometimes in large amounts. During smoking, THCA is partly converted to THC. The active isomer Δ8-THC, in which the unsaturated bond in the cyclohexene ring is located between C-8 and C-9, is found in much smaller amounts. Other closely related substances that occur in cannabis include cannabidiol (CBD) and, in aged samples, cannabinol (CBN), both of which have quite different pharmacological effects to THC.
- THC is the most known active component of cannabis. The pharmacology of cannabis is complicated by the presence of a wide range of cannabinoids. At small doses, cannabis produces euphoria, relief of anxiety, sedation and drowsiness. In some respects, the effects are similar to those caused by alcohol. Anandamide has been identified as the endogenous ligand for the cannabinoid receptor and has pharmacological properties similar to those of THC. When cannabis is smoked, THC can be detected in plasma within seconds of inhalation; it has a half-life of 2 hours. Following smoking of the equivalent of 10-15 mg over a period of 5-7 minutes, peak plasma levels of Δ9-THC are around 100 μg/L. It is highly lipophilic and widely distributed in the body. Two active metabolites are formed: 11-hydroxy-Δ9-THC and 8β-hydroxy-Δ9-THC. The first is further metabolized to Δ9-THC-11-oic acid. Two inactive substances are also formed—8α-hydroxy-Δ9-THC and 8α,11-dihydroxy-Δ9-THC and many other minor metabolites, most of which appear in the urine and feces as glucuronide conjugates. Some metabolites can be detected in the urine for up to 2 weeks following smoking or ingestion.
- Bioavailability following the smoking route was reported as 2-56%, due in part to intra- and inter-subject variability in smoking dynamics, which contributes to uncertainty in dose delivery. The number, duration, and spacing of puffs, hold time, and inhalation volume, or smoking topography, greatly influences the degree of drug exposure (Huestis M., “Human Cannabinoid Pharmacokinetics” Chem Biodivers. 2007 August; 4(8): 1770-1804).
- The chemical structure of Δ9-THC may be represented as Formula I:
- The chemical structure of CBN may be represented as Formula II:
- At least six CBN-type cannabinoids are known. With ring A aromatized, they may be formed as oxidation artifacts of THC and CBD, respectively. Their concentration in cannabis products may depend on age and storage conditions. CBN has been shown to induce drowsiness, and reduced time to sleep, but has been shown to create “hangover” symptoms when used alone for sleep.
- THC and CBN are known to be readily absorbed via the inhalation route, but very little is known about the biotransformation of CBN following oral administration and release in the gastrointestinal tract. Furthermore, to date, very little, if any, published information is available regarding the extent, or components of, biotransformation of cannabinoids, such as THC or CBN, following a delayed-release e.g. into the duodenum.
- The pharmaceutical formulations described herein are provided to meet the need in the art for oral dosage forms that provide controlled release into the gastrointestinal tract of a subject, in order to provide delivery of cannabinoid APIs described herein that in some embodiments may be useful for treating sleep disorders.
- In some embodiments, the present disclosure provides oral pulse-release compositions and dosage forms thereof, comprising a dose, e.g. a total daily dose, of one or more cannabinoid active pharmaceutical ingredients.
- The terms “pulse-release” or “pulsatile” formulation, as used herein refers in general to release of a portion of a total API dose, e.g. a portion of a total daily API dose, in a burst, followed by periods of little or no release (e.g., lag phase) in a defined temporal pattern. In particular, oral pulsatile drug release pertains to the burst delivery of drugs following a temporal pattern from the time of oral administration. In some embodiments, the pulse-release formulations of the present disclosure may combine a range of formulation approaches, including single- or multiple-unit immediate-release, delayed-release, and/or extended-release components. For example, in some embodiments, the delayed release components in the pulsatile formulations described herein may be configured to release an API at a desired site within the gastrointestinal tract, and/or release of the API after a defined time period. In some embodiments, an oral pulse-release dosage form of the present disclosure may comprise one or more immediate release oral pharmaceutical formulation components, one or more delayed release oral pharmaceutical formulation components, one or more extended release oral pharmaceutical formulation components, or any combinations thereof.
- In some embodiments, when administered orally to a subject, an oral pulse-release dosage form of the present disclosure is configured to provide release of a dosage, e.g. a daily dosage, of the one or more cannabinoids into the gastrointestinal tract of the subject, divided into at least 2 separate releases, or pulses separated by at least 2 hours, and not more than 6 hours, between releases. In some embodiments, when administered orally to a subject, an oral pulse-release dosage form of the present disclosure is configured to provide release of a dosage, e.g. a daily dosage, of the one or more cannabinoids into the gastrointestinal tract of the subject, divided into at least 3 separate releases, or pulses separated by at least 1 hours, and not more than 4 hours, between releases.
- In some embodiments, an oral pulse-release dosage form of the present disclosure may provide a total daily dose of a cannabinoid API, or a partial daily dose of a cannabinoid API. In some embodiment, a plurality, e.g. 2, 3, or more of the oral pulse-release dosage form of the present disclosure may be administered to a subject to provide a total daily dose. In some embodiments, the oral pulse-release dosage form of the present disclosure may be administered once, twice, three times or more, per day to provide a total daily dose of a cannabinoid API.
- In some embodiments, the pulse-release dosage forms of the present disclosure are configured to release a portion of an API in the gastric region (e.g. in the stomach), and the remaining portion in the small intestine e.g. distal duodenum, or other distal sites in the gastrointestinal tract.
- Accordingly, in some embodiments, the present disclosure provides an oral pulse-release dosage form, comprising a total dose, e.g. a total daily dose, of a cannabinoid active pharmaceutical ingredient (API), wherein the pulse-release dosage form comprises a first pulse-release component (C1) comprising a first portion (P1) of the cannabinoid API (API-P1), and at least a second pulse-release component (C2) comprising a second portion (P2) of the first cannabinoid API (API1P2). In the oral pulse-release dosage form, the total dose, e.g. total daily dose, of the API is divided between the first portion (P1) in the first pulse-release component (C1) and at least the second portion (P2) in the at least second pulse-release component (C2). When the pulse-release dosage form is placed in a simulated gastrointestinal environment, the pulse-release dosage form provides release of the API-P2 beginning from 2 to 6 hours after release of the API-P1 begins.
- The term “simulated gastrointestinal environment” is intended to be used herein to convey its ordinary meaning as understood in the art, and is understood in a broad sense to mean conditions that mimic oral administration, for example, an aqueous environment of low pH, 1-5 for example, followed after a period of up to about 2 hours with immersion in a higher pH aqueous environment, such as pH 6.8, for example, or a 3 stage environment in which the low pH is followed by an intermediate pH of about 6 wherein the environments are maintained at about 37.0° C. Alternatively, for certain embodiments a simulated gastrointestinal environment is described as the USP Apparatus I (Baskets) with agitation in which the composition is placed in 700 ml aqueous solution of 0.1N HCl pH 1.1, for up to 2 hours followed by 2-8 hours in sodium phosphate buffer at pH 6.0; followed by 6-20 hours in sodium phosphate buffer, pH 7.2, adding NaOH to adjust pH to 7.2. In some embodiments, the dissolution testing can include placing a dosage form in an aqueous solution of 0.1N HCl pH 1.1 for 2 hours followed by 8 hours in sodium phosphate buffer at pH 6.8, at 37° C.±0.5° C., and sampling at appropriate time intervals, e.g. at 1, 1.5, 2, 3, 3.5, 4, 5, 6, 7, 8, 9 and 10 hours.
- For example, a two-stage dissolution test is described in USP General Chapter <711>Dissolution, in which the integrity of an enteric coating is determined in an acidic environment and the drug release is measured in a neutral environment. The test can be performed using either medium-addition or medium exchange methods; both may start with an acid stage in 0.1 N hydrochloric acid for two hours and follow with a buffer stage in phosphate buffer at pH 6.8 for e.g. 45 min or a specific time as needed for the individual drug product. Medium addition or medium exchange procedures may be used. For the medium-addition approach, a designated amount of concentrated phosphate buffer may be added to the dissolution vessel to neutralize the medium to the target pH before the buffer stage starts. The operations of adding the buffer and adjusting the pH may be completed within 5 min. For the medium-exchange approach, the acid medium may be drained after two hours, and a full amount of pH 6.8 buffer may be added to the same vessel for the buffer stage. The dosage unit is typically left undisturbed during the medium change. Alternatively, the vessel containing the acid can be removed and replaced with another vessel containing the buffer, and the dosage unit transferred to the new vessel.
- Parameters of suitable API-specific biorelevant dissolution methods such as in vitro dissolution analysis can be determined by skilled persons without undue experimentation upon reading the present disclosure. For example, and without limitation, an in-vitro non-sink, gastric transfer dissolution method may be used to analyze the release and dissolution of API.
- At pre-determined time points, samples may be drawn from the dissolution vessel and centrifuged using an ultracentrifuge. The supernatants may be further diluted using an HPLC diluent and analyzed by a suitable HPLC method. Parameters such as peak release rate (PRR) and the area under drug dissolution curve (AUDC), among others, may be calculated, e.g. by the linear trapezoidal method.
- Each of the pulse-release components that may be combined to provide the oral pulse-release dosage form may be analyzed separately by in vitro dissolution tests, to determine the pulse-release timing for each pulse-release component of the oral pulse-release dosage form. The “beginning” of release from a pulse-release component may be defined as the time at which a detectable amount of the API is present in the dissolution media, or when a certain percentage of the total dose is detected in the dissolution media, e.g. at least 1%, 5%, or 10% of the total amount of the API present in the particular pulse-release component.
- For example, in some embodiments, the simulated gastrointestinal environment may be an aqueous solution of 0.1N HCl pH 1.1 for 2 hours followed by 8 hours in sodium phosphate buffer at pH6.8, at 37° C.±0.5° C.
- In some embodiments, when the pulse-release dosage form is placed in a simulated gastrointestinal environment, the pulse-release dosage form may provide a second time of peak release rate (PRR2) of the API from about 2 to 6 hours after a first time of peak release rate (PRR1). For example,
FIG. 1 and Example 3 describe example in vitro dissolution data of an example pulse-release dosage form of the present disclosure. In some embodiments, when the pulse-release dosage form is placed in a simulated gastrointestinal environment, a first time of PRR of the API may be after 1-2 hours, and a second time of PRR may be from about 2 to 6 hours after the first time of PRR. - In some embodiments, the pulse-release dosage form may comprise a total dose, e.g. a total daily dose, of a cannabinoid API from 1 mg to 100 mg, for example, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 mg.
- In some embodiments, the first pulse-release component (C1) may be an immediate release (IR) formulation of the cannabinoid API. For example, an IR formulation of the API may include, without limitation, the first portion (P1) of the cannabinoid API (API-P1), as well as one or more binders, one or more disintegrants, one or more lubricants, one or more flow aids, or any combinations thereof. In some embodiments, the second pulse-release component (C2) may be a delayed release (DR) formulation of the cannabinoid API. For example, a DR formulation of the API may include, without limitation, the second portion (P2) of the cannabinoid API (API-P2), as well as one or more binders, one or more lubricants, one or more flow aids, or any combinations thereof, and the second pulse-release component may be coated with a layer of one or more pH-dependent or non-pH-dependent polymers, one or more plasticizers, or both.
- In some embodiments, the binder may include, but is not limited to, microcrystalline cellulose, corn starch, pregelatinized starch, potato starch, rice starch, sodium carboxymethyl starch, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, ethylcellulose, chitosan, hydroxychitosan, hydroxymethylatedchitosan, cross-linked chitosan, cross-linked hydroxymethyl chitosan, maltodextrin, mannitol, sorbitol, dextrose, maltose, fructose, glucose, levulose, sucrose, polyvinylpyrrolidone (PVP), acrylic acid derivatives (Carbopol, Eudragit, etc.), polyethylene glycols, such a low molecular weight PEGs (PEG2000-10000) and high molecular weight PEGs (Polyox) with molecular weights above 20,000 daltons.
- In some embodiments, the binders may be present in a pulse-release component of the pulse-release dosage form in the range of 1.0 to 60% (W/W).
- In addition, other ingredients that may be included in a pulse-release component of the pulse-release dosage form to aid in the dissolution of the API, or the breakdown of the pulse-release component after ingestion or administration may include, without limitation, one or more surfactants, such as sodium lauryl sulfate, sodium monoglycerate, sorbitan monooleate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, glyceryl monostearate, glyceryl monooleate, glyceryl monobutyrate, a non-ionic surfactant such as the Pluronic line of surfactants, or any other material with surface active properties.
- In some embodiments, the disintegrant may include, but is not limited to, sodium starch glycolate, corn starch, rice starch, gar gum, polyvinylpolypyrrolidone, croscarmellose, and hydroxypropylmethylcellulose, among others.
- In some embodiments, the disintegrants may be present in a pulse-release component of the pulse-release dosage form in the range of 0.05-15% (W/W).
- In some embodiments, the lubricant may include, but is not limited to, magnesium stearate, calcium stearate, and stearic acid, among others.
- In some embodiments, the lubricants may be present in a pulse-release component of the pulse-release dosage form in the range of 0.05-5% (W/W).
- In some embodiments, the flow aid may include, but is not limited to, colloidal silicone dioxide, and magnesium stearate, among others.
- In some embodiments, the flow aids may be present in a pulse-release component of the pulse-release dosage form in the range of 0.05-0.5% (W/W).
- In some embodiments, the polymer coating may include, but is not limited to, one or more pH-dependent or non-pH-dependent excipients. Examples of non-pH dependent polymers include ethyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, copolymer of ethyl acrylate, methyl methacrylate (e.g., Eudragit R S), among others. Examples of pH-dependent excipients include methacrylic acid copolymers, hydroxypropylmethyl cellulose acetate succinate, hydroxypropylmethyl cellulose phthalate, and cellulose acetate phthalate, among others. The pH-dependent polymer coating may also include a pore former, such as povidone, polyethylene glycol, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, among others, sugars such as sucrose, mannitol, lactose, and salts, such as sodium chloride, sodium citrate, among others. In some embodiments, the polymer coating may include a plasticizer, such as acetylated citrated esters, acetylated glycerides, castor oil, citrate esters, dibutylsebacate, glyceryl monostearate, diethyl phthalate, glycerol, medium chain triglycerides, propylene glycol, and polyethylene glycol. The coating may also include one or more additional excipients, such as lubricants (e.g., magnesium stearate, talc among others). The coating can be applied using conventional coating techniques such as fluidized bed coating, pan coating, among others.
- In certain embodiments, the pH-dependent polymer can be a pharmaceutically acceptable acrylic polymer, including but not limited to, acrylic acid and methacrylic acid copolymers, methyl methacrylate, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid), poly (methacrylic acid), methacrylic acid alkylamine copolymer poly(methyl methacrylate), poly(methacrylic acid)(anhy-dride), polymethacrylate, polyacrylamide, poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers. In certain other embodiments, the acrylic polymer is comprised of one or more ammonia methacrylate copolymers. Ammonio methacrylate copolymers are well known in the art, and are described as fully polymerized copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups. In still other embodiments, the acrylic polymer may be an acrylic resin lacquer such as a Eudragit®. In further embodiments, the acrylic polymer comprises a mixture of two acrylic resin lacquers commercially available from Evonik/Rohm Pharma under the trade names Eudragit® RL30D and Eudragit® RS30D, respectively. Eudragit® RL30D and Eudragit® RS30D are copolymers of acrylic and methacrylic esters with a low content of quaternary ammonium groups, the molar ratio of ammonium groups to the remaining neutral (meth)acrylic esters being 1:20 in Eudragit® RL30D and 1:40 in Eudragit® RS30D. Eudragit® S-100 and Eudragit® L-100 are also suitable for use herein. The code designations RL (high permeability) and RS (low permeability) refer to the permeability properties of these agents. Eudragit® mixtures are insoluble in water and in digestive fluids. However, multi-particulate systems formed to include the same are swellable and permeable in aqueous solutions and digestive fluids. The polymers described above such as Eudragit® RL/RS may be mixed together in any desired ratio in order to ultimately obtain an extended release formulation having a desirable dissolution profile. One skilled in the art will recognize that other acrylic polymers may also be used, such as, for example, Eudragit® L.
- In some embodiments, the polymer coatings may be present in a pulse-release component of the pulse-release dosage form in the range of 0.5-35% (W/W).
- In some embodiments, the pulse-release dosage form may include API coated cores. In some embodiments, the cores may comprise non-pareils or sugar spheres.
- In some embodiments, the pulse-release dosage form may optionally comprise a seal coat. In some embodiments, a DR pulse-release component of the pulse-release dosage form may be coated with a polymer coating by fluidized bed coating.
- In some embodiments, a pulse-release component of the present disclosure can be prepared by any suitable method known in the art, such as mixing the ingredients in a suitable pharmaceutical mixer or granulator such as a planetary mixer, high-shear granulator, fluid bed granulator, or extruder, in the presence of water or other solvent, or in a hot melt process. If water or other solvent is used, the blend may be dried in a suitable pharmaceutical drier, such as a vacuum oven or forced-air oven. After allowing the product to cool, the product may be sieved or granulated, and compressed using a suitable tablet press, such as a rotary tablet press.
- A pharmaceutical formulation of the present disclosure may be further processed into a solid dosage form suitable for oral administration, such as a pill, tablet or capsule. In some embodiments, the pharmaceutical formulation of the present disclosure may be provided in oral dosage forms such as a syrup, film, orally-disintegrating tablet, a liquid solution or suspension (e.g., drink or syrup), a powder, or liquid or solid crystals, or a paste.
- An example method of formulating an example pulse-release oral dosage form of the present disclosure is described in Example 2.
- In some embodiments, in the oral pulse-release dosage form of the present disclosure, where the dosage, e.g. the daily dosage, of the API is divided into at least 2 separate releases, the percentage of API released from the first portion (P1) may be from 25% to 75% of the total dose, e.g. the total daily dose, and the percentage of API released from the second portion (P2) may be from 25% to 75% of the total dose, e.g. the total daily dose.
- In certain embodiments, the cannabinoid API may be THC. In certain embodiments, the cannabinoid API may be CBN.
- In some embodiments, in the oral pulse-release dosage form, the first pulse-release component (C1) may include from at least 2.5 mg to at least 30 mg THC. In some embodiments, in the oral pulse-release dosage form, the first pulse-release component (C1) may include from at least 1.25 mg to at least 75 mg CBN. In some embodiments, in the oral pulse-release dosage form, the second pulse-release component (C2) may include from at least 2.5 mg to at least 30 mg THC. In some embodiments, in the oral pulse-release dosage form, the second pulse-release component (C2) may include from at least 1.25 mg to at least 75 mg CBN.
- In some embodiments, the oral pulse-release dosage form of the present disclosure may include a first cannabinoid API and a second cannabinoid API. Accordingly, in some embodiments, the oral pulse-release dosage form may include a total dose, e.g. a total daily dose of a first cannabinoid active pharmaceutical ingredient (API1) and a total dose e.g a total daily dose of a second cannabinoid API (API2), wherein the pulse-release dosage form comprises: a first pulse-release component (C1) comprising a first portion (P1) of the first cannabinoid API (API1P1) and a first portion (P1) of the second cannabinoid API (API2P1); and at least a second pulse-release component (C2) comprising a second portion (P2) of the first cannabinoid API (API1P2) and a second portion (P2) of the second cannabinoid API (API2P2). In the oral pulse-release dosage form, the total dose e.g the total daily dose of each of the API1 and the API2 is divided between the first portion (P1) in the first pulse-release component (C1) and at least the second portion (P2) in the at least second pulse-release component (C2). When the pulse-release dosage form is placed in a simulated gastrointestinal environment, e.g. an aqueous solution of 0.1N HCl pH 1.1 for 2 hours followed by 8 hours in sodium phosphate buffer at pH 6.8, at 37° C.±0.5° C., the pulse-release dosage form provides release of the API1P2 and the API2P2 beginning from 2 to 6 hours after release of the API1P1 and the API2P1 begins.
- In some embodiments, when the pulse-release dosage form is placed in a simulated gastrointestinal environment, the pulse-release dosage form may provide a second time of peak release rate (PRR2) of each of the API1 (PRR2API1) and the API2 (PRR2API2) from about 2 to 6 hours after a first time of peak release rate (PRR1). In some embodiments, the PRR1 may be after 1-2 hours.
- In some embodiments, the first cannabinoid API1 may be THC and the second cannabinoid API2 may be cannabinol (CBN), and the total dose, e.g. the total daily dose, of the THC is from 1 mg to 40 mg and the total dose, e.g. the total daily dose of the CBN is from 2.5 mg to 100 mg.
- In some embodiments, the first cannabinoid API1 may be THC and the second cannabinoid API2 may be CBN, and the total dose, e.g. the total daily dose, of the THC is selected from: at least 1 mg, at least 2 mg, at least 3 mg, at least 4 mg, at least 5 mg, at least 6 mg, at least 8 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, and at least 35 mg, and the total dose e.g. the total daily dose, of the CBN is selected from: at least 2.5 mg, at least 3 mg, at least 4 mg, at least 5 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, and at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, and at least 95 mg.
- In some embodiments, the first pulse-release component (C1) may be an immediate release (IR) formulation of the first cannabinoid API1 and the second cannabinoid API2, comprising the first portion (P1) of the first cannabinoid API (API1P1) and the first portion (P1) of the second cannabinoid API (API2P1). In some embodiments, the second pulse-release component (C2) may be a delayed release (DR) formulation of the first cannabinoid API1 and the second cannabinoid API2, comprising the second portion (P2) of the first cannabinoid API (API1P2) and a second portion (P2) of the second cannabinoid API (API2P2).
- In some embodiments, for each API, the first portion (P1) may be independently selected from 25% to 75% of the total dose, e.g. the total daily dose, and for each API the second portion (P2) may be independently selected from 25% to 75% of the total dose, e.g. the total daily dose.
- In some embodiments, the first pulse-release component (C1) may comprise from 0.5 mg to 30 mg of the first cannabinoid active pharmaceutical ingredient (API1), wherein the API1 is THC, and from 1.25 mg to 75 mg of the second cannabinoid active pharmaceutical ingredient (API1), wherein the API1 is CBN. The second pulse-release component (C2) may comprise from 0.5 mg to 30 mg of the first cannabinoid active pharmaceutical ingredient (API1), wherein the API1 is THC, and from 1.25 mg to 75 mg of the second cannabinoid active pharmaceutical ingredient (API1), wherein the API1 is CBN.
- In some embodiments, the daily dosage is at least 1 mg THC and at least 10 mg CBN. In some embodiments, the daily dosage is at least 2 mg THC and at least 20 mg CBN. In some embodiments, the daily dosage is at least 4 mg THC and at least 40 mg CBN. In some embodiments, the daily dosage is at least 5 mg THC and at least 2.5 mg CBN. In some embodiments, the daily dosage is at least 6 mg THC and at least 3 mg CBN. In some embodiments, the daily dosage is at least 8 mg THC and at least 4 mg CBN. In some embodiments, the daily dosage is at least 5 mg THC and at least 10 mg CBN. In some embodiments, the daily dosage is at least 10 mg THC and at least 10 mg CBN. In some embodiments, the daily dosage is at least 20 mg THC and at least 10 mg CBN. In some embodiments, the daily dosage is at least 20 mg THC and at least 20 mg CBN. In some embodiments, the daily dosage is at least 10 mg THC and at least 20 mg CBN. In some embodiments, the daily dosage is at least 10 mg THC and at least 25 mg CBN. In some embodiments, the daily dosage is at least 10 mg THC and at least 30 mg CBN. In some embodiments, the daily dosage is at least 10 mg THC and at least 40 mg CBN.
- Example formulations of the pulse-release oral dosage forms of the present disclosure are provided in Example 1.
- In some embodiments, the oral pulse-release dosage form comprises a total dose e.g. a total daily dose of a first cannabinoid active pharmaceutical ingredient (API1) and a total dose e.g. a total daily dose of a second cannabinoid API (API2), wherein the pulse-release dosage form comprises a first pulse-release component (C1) comprising a first portion (P1) of the first cannabinoid API (API1P1) and a first portion (P1) of the second cannabinoid API (API2P1), a second pulse-release component (C2) comprising a second portion (P2) of the first cannabinoid API (API1P2) and a second portion (P2) of the second cannabinoid API (API2P2), and at least a third pulse-release component (C3) comprising a third portion (P3) of the first cannabinoid API (API1P3) and a third portion (P3) of the second cannabinoid API (API2P2). In the oral pulse-release dosage form, the total dose e.g. the total daily dose of each of the API1 and the API2 is divided between the first portion (P1) in the first pulse-release component (C1), the second portion (P2) in the second pulse-release component (C2), and at least the third portion (P3) in the at least third pulse-release component (C3). When the pulse-release dosage form is placed in an aqueous solution of 0.1N HCl pH 1.1 for 2 hours followed by 8 hours in sodium phosphate buffer at pH 6.8, at 37° C.±0.5° C., the pulse-release dosage form provides release of the API1P2 and the API2P2 beginning from 1 to 4 hours after release of the API1P1 and the API2P1 begins, and release of the API1P3 and the API2P3 beginning from 1 to 4 hours after release of the API1P2 and the API2P2 begins.
- In some embodiments, the oral pulse-release dosage form provides a second time of peak release rate (PRR2) of each of the API1 (PRR2API1) and the API2 (PRR2API2) from about 1 to 4 hours after a first time of peak release rate (PRR1) and a third time of peak release rate (PRR3) of each of the API1 (PRR3API1) and the API2 (PRR3API2) from about 1 to 4 hours after the second time of peak release rate (PRR2). In some embodiments, the PRR1 is after 1-2 hours.
- In some embodiments, when the oral pulse-release dosage form provides release of a dosage, e.g. a daily dosage, of the API1 and the API2 into the gastrointestinal tract of the subject, divided into at least 3 separate releases, the first cannabinoid API1 may be THC and the second cannabinoid API2 may be CBN. The total dose, e.g. the total daily dose, of the THC may be from 10 mg to 40 mg and the total dose e.g. the total daily dose of the CBN may be from 5 mg to 100 mg. In some embodiments, the first cannabinoid API1 is THC and the second cannabinoid API2 is CBN, and the total dose e.g. the total daily dose of the THC is selected from: at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, and at least 35 mg, and the total dose e.g. the total daily dose of the CBN is selected from: at least 5 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, and at least 95 mg.
- In some embodiments, the first pulse-release component (C1) may be an immediate release (IR) formulation of the first cannabinoid API1 and the second cannabinoid API2, comprising the first portion (P1) of the first cannabinoid API (API1P1) and a first portion (P1) of the second cannabinoid API (API2P1). The second pulse-release component (C2) may be a delayed release (DR) formulation of the first cannabinoid API1 and the second cannabinoid API2, comprising the second portion (P2) of the first cannabinoid API (API1P2) and a second portion (P2) of the second cannabinoid API (API2P2). The third pulse-release component (C3) may be a delayed release (DR) formulation of the first cannabinoid API1 and the second cannabinoid API2, comprising the third portion (P3) of the first cannabinoid API (API1P3) and a third portion (P3) of the second cannabinoid API (API2P3). The second pulse-release component may be coated with a first delayed-release layer comprising one or more pH-dependent and/or non-pH-dependent polymers, and optionally one or more plasticizers, one or more pore formers, and/or one or lubricants. The third pulse-release component may be coated with a second delayed-release layer comprising one or more pH-dependent and/or non-pH-dependent polymers, and optionally one or more plasticizers, one or more pore formers, and/or one or lubricants. The second delayed-release layer may provide a delayed release of 1-4 hours longer than the first delayed-release layer.
- In some embodiments, for each API, the first portion (P1) may be independently selected from 25% to 75% of the total dose e.g. the total daily dose, for each API, the second portion (P2) may be independently selected from 25% to 75% of the total dose e.g. the total daily dose, and, for each API, the third portion (P3) may be independently selected from 25% to 75% of the total dose e.g. the total daily dose.
- In some embodiments, the first pulse-release component (C1) may include from 2.5 mg to 30 mg of the first cannabinoid active pharmaceutical ingredient (API1), wherein the API1 is THC, and from at least 1.25 mg to 75 mg of the second cannabinoid active pharmaceutical ingredient (API1), wherein the API1 is CBN. The second pulse-release component (C2) may include from 2.5 mg to 30 mg of the first cannabinoid active pharmaceutical ingredient (API1), wherein the API1 is THC, and from 1.25 mg to 75 mg of the second cannabinoid active pharmaceutical ingredient (API1), wherein the API1 is CBN. The third pulse-release component (C3) may include from 2.5 mg to 30 mg of the first cannabinoid active pharmaceutical ingredient (API1), wherein the API1 is THC, and from 1.25 mg to 75 mg of the second cannabinoid active pharmaceutical ingredient (API1), wherein the API1 is CBN.
- In some embodiments, the present disclosure provides a method of treating a sleep disorder in a subject in need thereof, the method comprising administering to the subject an oral pulse-release dosage form of the present disclosure. In some embodiments, the administering may be up to 30 minutes, up to 1 hour, or up to 2 hours before the subject intends to begin sleeping at night.
- The description herein is primarily directed to treatment of sleep disorders in subjects with a typical schedule, wherein the subject intends to go to sleep starting from around 9 P.M. to about midnight, for example. Accordingly, terms used herein such as “at night”, “during the night” and so on are intended to refer to the usual period of time when the subject intends to be asleep, and, similarly, terms such as “in the morning” are intended to refer to a period after the subject's usual sleeping time. It is understood, however, that the use and efficacy of the compositions and methods described herein, is not limited to such a schedule, but can be adopted for use with different daily schedules, such as night workers, or people with more variable sleep patterns.
- In some embodiments, the term sleep disorder as used herein more particularly refers to insomnia. Insomnia may include a difficulty falling asleep or staying asleep, or both. In some embodiments, the sleep disorder may be characterized primarily or predominantly by various symptoms, such as difficulty falling asleep or may be characterized primarily or predominantly by difficulty staying asleep, either in an individual subject, or in a group of subjects, such as a population of subjects. In some embodiments, the sleep disorder may include, without limitation, one or more of insufficient total sleeping time during the night, increased frequency of awakenings during the night, increased number of times out of bed at night, increased time awake at night, increased latency to sleep onset, deviations from proportions of time or duration of time in light sleep, deep sleep and/or REM sleep compared to those typically seen in individuals that do not experience insomnia, and the insomnia may produce a number of effects, such as not feeling well rested in the morning and/or during the day, decreased sleep satisfaction, increase in number of naps during the day, decreased wakefulness during daytime activities such as during work or school, or any combinations thereof.
- In some embodiments, administering a subject in need of treatment for a sleep disorder with an oral pulse-release dosage form of the present disclosure may provide effective treatment of one or more aspects of the subject's sleep disorder.
- For example, as described in Example 4, an example pulse-release dosage form comprising two example cannabinoid API's, THC and CBN provided effective treatment of insomnia in a group of subjects. In particular, the subjects in the study described in Example 4 experienced insomnia, primarily or predominantly characterized by difficulty staying asleep at night. Traditional sleep aids were marginally effective, and had a profound impact on quality of sleep, and in particular REM and deep sleep components of their sleep experience. The example formulation provided the subjects with longer sleep duration, and no deleterious effects on REM and deep sleep components of the sleep experience. In addition, surprisingly, the subjects experienced few residual effects (or “hangover”) of the treatment. This is in stark contrast to other drugs commonly used for sleep disorders
- Surprisingly, the treatment did not affect all aspects of the subjects' sleep experience equally. For example, there was no effect on objective measures of latency to sleep onset, number of awakenings during the night, and no increase in time in REM sleep or deep sleep.
- Recent studies indicate that individuals using cannabis expect it to decrease their sleep-related problems (Altman et al., 2019) and are likely to reduce their use of sleep medications (Piper et al., 2017). Participants in the study by Altman and colleagues (2019) reported that using cannabis helped them fall asleep about 15 minutes faster and sleep for about 2 hours longer. Nonetheless, previous studies have shown that the optimal concentration, dosage, timing, and route of administration for treating sleep disorders remain unknown (Babson et al., 2017).
- Unexpectedly, as described in Example 5, and in contrast to the findings described in Example 4, administering subjects reporting difficulty in falling asleep with the same dosage of 10 mg THC and 5 mg CBN, but delivered in an immediate release dosage form via the sublingual route, did not result in any objectively measured improvements in any aspect of sleep. To the contrary, surprisingly, 10 mg THC and 5 mg CBN delivered in an immediate release dosage form via the sublingual route significantly increased the time to fall asleep in these subjects.
- Therefore, not all administration routes or dosage forms of cannabinoids, or dosage timing, may be expected to be useful for treating subjects experiencing insomnia. In addition, not all symptoms of insomnia may be effectively or equally treated by administering a subject with various formulations of cannabinoids.
- Accordingly, the oral pulse-release compositions and dosage forms described herein may provide particular advantages as compared to other medications for treating sleep disorders.
- In some embodiments, administering a subject in need of treatment for a sleep disorder with an oral pulse-release dosage form of the present disclosure may result in an increase in the subject's total sleeping time during the night.
- In some embodiments, the administering may result in an increase in the subject's total light sleeping time during the night.
- In some embodiments, the administering may result in an increase in the subject's light sleeping time as a proportion of total sleeping time during the night.
- In some embodiments, the administering may result in an increase in the subject's total time in bed during the night.
- In some embodiments, the effects of the administering on the subject may be measured using a SleepScore Max® system (e.g., see Example 4).
- In some embodiments, the administering may result in an increase in SleepScore number as determined using a SleepScore Max® system.
- In some embodiments, the administering may result in the subject experiencing an increase in feeling well rested in the morning and/or during the day, perceived sleep quality, perceived total sleep time during the night, sleep satisfaction, or any combinations thereof. The administering may result in the subject experiencing a decrease in perceived frequency of awakenings during the night, number of times out of bed at night, number of naps during the day, or perceived time awake at night, or any combinations thereof.
- In some embodiments, the subject in need of treatment may be experiencing insomnia that is primarily characterized by an inability to stay asleep during the night. In some embodiments, the insomnia may be characterized using objective measurements, e.g. using a SleepScore Max® system. In some embodiments, characterization of the sleep disorder is reported by the subject, e.g. identified subjectively, or without using objective analysis e.g. using a SleepScore Max® system.
- In some embodiments, the administering may not result in a decrease in latency to sleep onset, an alteration of time in deep sleep and/or REM sleep, a hangover effect during the day after the administering, or any combinations thereof.
- In some embodiments, the administering may result in a decrease in latency to sleep onset.
- In some embodiments, the subject may have been previously been administered with one or more cannabinoids for treating a medical condition. For example, the subject may have previously used medical marijuana for one or more medical conditions.
- The term “subject” as used herein refers to a warm blooded animal such as a mammal which is treated for a condition that causes at least one symptom. It is understood that at least humans, dogs, cats, and horses are within the scope of the meaning of the term. In some embodiments, the subject is a human. In particular, the subject may be in need of treatment for a sleep disorder, e.g. insomnia.
- As used herein, the term “treat” or “treatment”, or a derivative thereof, contemplates partial or complete amelioration of at least one symptom associated with the condition of the subject.
- The present examples are provided for illustrative purposes only. They are not intended to and should not be interpreted to encompass the full breadth of the disclosure.
- This Example provides example formulations of a pulse-release THC and CBN oral dosage forms of the present disclosure.
-
-
First pulse-release component THC 5 mg 5.7% CBN 2.5 mg 2.8% Microcrystalline Cellulose 65 mg 73.9 % Hydroxypropylmethylcellulose 15 mg 17.0% Magnesium stearate 0.5 mg 0.6% Total 88.0 mg 100.0% Second pulse-release component THC 5 mg 3.8% CBN 2.5 mg 1.9% Microcrystalline Cellulose 95 mg 71.4% Methacrylic acid copolymer 30 mg 22.6% Magnesium stearate 0.25 mg 0.2% Colloidal silicone dioxide 0.25 mg 0.2% Total 133.0 mg 100.0% -
-
First pulse-release component THC 5 mg 5.4% CBN 2.5 mg 2.7% Microcrystalline Cellulose 65 mg 70.7 % Hydroxypropylmethylcellulose 10 mg 10.8% Lactose 5 mg 5.4% Sodium starch glycolate 4 mg 4.3% Magnesium stearate 0.5 mg 0.5% Total 92.0 mg 100.0% Second pulse-release component THC 5 mg 3.0% CBN 2.5 mg 1.5 % Microcrystalline Cellulose 120 mg 71.1% Methacrylic acid copolymer 40 mg 23.7% Magnesium stearate 0.7 mg 0.4% Colloidal silicone dioxide 0.5 mg 0.3% Total 168.7 mg 100.0% - This is an example of a first pulse-release component that may be combined with any second pulse-release component described herein, e.g. may be combined with the second pulse-release component of Example 1(b) in some embodiments.
-
THC 3.27% 10 mg CBN 1.63% 5 mg Sugar Spheres 20.60% 63 mg Microcrystalline cellulose 200 16.50% 50.5 mg Microcrystalline cellulose 302 24.10% 73.7 mg Croscarmellose sodium 5.80% 17.7 mg Isomalt 24.20% 74 mg FD&C Blue # 20.30% 0.9 mg Silicone dioxide 0.50% 1.5 mg Magnesium stearate 1.00% 3.1 mg Non-functional coating 2.10% 6.4 mg 100.00% 305.8 mg - This is an example of a first pulse-release component that may be combined with any second pulse-release component described herein, e.g. may be combined with the second pulse-release component of Example 1(b) in some embodiments.
-
THC 3.27% 10 mg CBN 1.63% 5 mg Sugar Spheres 20.60% 63 mg Microcrystalline cellulose 200 16.50% 50.5 mg Microcrystalline cellulose 302 24.10% 73.7 mg Croscarmellose sodium 5.80% 17.7 mg Isomalt 24.20% 74 mg FD&C Blue # 20.30% 0.9 mg Silicone dioxide 0.50% 1.5 mg Magnesium stearate 1.00% 3.1 mg Non-functional coating 2.10% 6.4 mg 100.00% 305.8 mg -
-
First pulse-release component THC 5 mg 4.6% CBN 2.5 mg 2.3% Lactose 85 mg 78.7 % Polyvinylpyrrolidone 10 mg 9.2% Polyvinylpolypyrrolidone 5 mg 4.6% Magnesium stearate 0.5 mg 0.5% Total 108.0 mg 100.0% Second pulse-release component THC 5 mg 3.8% CBN 2.5 mg 1.9% Microcrystalline Cellulose 95 mg 71.4% Methacrylic acid copolymer 30 mg 22.6% Magnesium stearate 0.25 mg 0.2% Colloidal silicone dioxide 0.25 mg 0.2% Total 133.0 mg 100.0% -
-
First pulse-release component THC 10.0 mg 5.3% CBN 5.0 mg 2.7% Microcrystalline Cellulose 125.0 mg 66.8% Hydroxypropylmethylcellulose 35.0 mg 18.7 % Croscarmellose Sodium 11 mg 5.9% Magnesium stearate 1.2 mg 0.6% Total 187.2 mg 100.0% Second pulse-release component THC 5 mg 3.8% CBN 2.5 mg 1.9% Microcrystalline Cellulose 95 mg 71.4% Methacrylic acid copolymer 30 mg 22.6% Magnesium stearate 0.25 mg 0.2% Colloidal silicone dioxide 0.25 mg 0.2% Total 133.0 mg 100.0% -
-
First pulse-release component THC 10.0 mg 5.3% CBN 5.0 mg 2.7% Microcrystalline Cellulose 125.0 mg 66.8% Hydroxypropylmethylcellulose 35.0 mg 18.7 % Croscarmellose Sodium 11 mg 5.9% Magnesium stearate 1.2 mg 0.6% Total 187.2 mg 100.0% Second pulse- release component THC 10 mg 3.6% CBN 5 mg 1.8% Microcrystalline Cellulose 200 mg 71.2% Methacrylic acid copolymer 65 mg 23.1% Magnesium stearate 0.5 mg 0.2% Colloidal silicone dioxide 0.5 mg 0.2% Total 281.0 mg 100.0% -
-
First pulse-release component THC 10.0 mg 5.3% CBN 5.0 mg 2.7% Microcrystalline Cellulose 125.0 mg 66.8% Hydroxypropylmethylcellulose 35.0 mg 18.7 % Croscarmellose Sodium 11 mg 5.9% Magnesium stearate 1.2 mg 0.6% Total 187.2 mg 100.0% Second pulse-release component THC 20.0 mg 6.1% CBN 10.0 mg 3.0% Microcrystalline Cellulose 225.0 mg 68.3% Methacrylic acid copolymer 72.0 mg 21.9% Magnesium stearate 1.5 mg 0.5% Colloidal silicone dioxide 0.75 mg 0.2% Total 329.3 mg 100.0% -
-
First pulse-release component THC 5.0 mg 5.3% CBN 10.0 mg 2.7% Microcrystalline Cellulose 125.0 mg 66.8 % Croscarmellose Sodium 11 mg 5.9% Magnesium stearate 1.2 mg 0.6% Total 187.2 mg 100.0% Second pulse-release component THC 5.0 mg 3.8% CBN 10.0 mg 1.9% Microcrystalline Cellulose 215.0 mg 71.4% Hydroxypropylmethylcellulose acetate 57.0 mg 22.6% Magnesium stearate 1.5 mg 0.2% Colloidal silicone dioxide 0.75 mg 0.2% Total 289.25 mg 100.0% -
-
First pulse-release component THC 10.0 mg 4.7% CBN 10.0 mg 4.7% Microcrystalline Cellulose 135.0 mg 63.2% Hydroxypropylmethylcellulose 41.3 mg 19.3% Croscarmellose Sodium 16 mg 7.5% Magnesium stearate 1.2 mg 0.6% Total 213.5 mg 100.0% Second pulse-release component THC 5.0 mg 2.7% CBN 10.0 mg 5.4% Microcrystalline Cellulose 125.0 mg 70.0% Methacrylic acid copolymer 43.0 mg 23.4% Magnesium stearate 0.6 mg 0.3% Colloidal silicone dioxide 0.3 mg 0.2% Total 183.9 mg 100.0% -
-
First pulse-release component THC 10.0 mg 4.7% CBN 10.0 mg 4.7% Microcrystalline Cellulose 135.0 mg 63.2% Hydroxypropylmethylcellulose 41.3 mg 19.3% Croscarmellose Sodium 16 mg 7.5% Magnesium stearate 1.2 mg 0.6% Total 213.5 mg 100.0% Second pulse-release component THC 5.0 mg 2.7% CBN 10.0 mg 5.4% Microcrystalline Cellulose 125.0 mg 70.0% Cellulose Acteate Pthalate 43.0 mg 23.4% Magnesium stearate 0.6 mg 0.3% Third pulse-release component THC 5.0 mg 2.7% CBN 10.0 mg 5.4% Microcrystalline Cellulose 125.0 mg 70.0% Methacrylic acid copolymer 43.0 mg 23.4% Magnesium stearate 0.6 mg 0.3% -
-
First pulse-release component THC 2.5 mg 1.3% CBN 1.25 mg 0.6% Microcrystalline Cellulose 135.0 mg 68.4% Hydroxypropylmethylcellulose 41.3 mg 20.9% Croscarmellose Sodium 16 mg 8.1% Magnesium stearate 1.2 mg 0.6% Total 197.25 mg 100.0% Second pulse-release component THC 2.5 mg 1.4% CBN 1.25 mg 0.7% Microcrystalline Cellulose 125.0 mg 72.4% Methacrylic acid copolymer 43.0 mg 24.9% Magnesium stearate 0.6 mg 0.3% Colloidal silicone dioxide 0.3 mg 0.2% Total 172.65 mg 100.0% -
-
First pulse-release component THC 3.0 mg 1.5% CBN 1.5 mg 0.8% Microcrystalline Cellulose 135.0 mg 68.2% Hydroxypropylmethylcellulose 41.3 mg 20.9% Croscarmellose Sodium 16.0 mg 8.1% Magnesium stearate 1.2 mg 0.6% Total 198.0 mg 100.0% Second pulse-release component THC 3.0 mg 1.7% CBN 1.5 mg 0.9% Microcrystalline Cellulose 125.0 mg 72.1% Methacrylic acid copolymer 43.0 mg 24.8% Magnesium stearate 0.6 mg 0.3% Colloidal silicone dioxide 0.3 mg 0.2% Total 173.4 mg 100.0% -
-
First pulse-release component THC 4.0 mg 2.0% CBN 2.0 mg 1.0% Microcrystalline Cellulose 135.0 mg 67.7% Hydroxypropylmethylcellulose 41.3 mg 20.7% Croscarmellose Sodium 16 mg 8.0% Magnesium stearate 1.2 mg 0.6% Total 199.5 mg 100.0% Second pulse-release component THC 4.0 mg 2.3% CBN 2.0 mg 1.1% Microcrystalline Cellulose 125.0 mg 71.5% Methacrylic acid copolymer 43.0 mg 24.6% Magnesium stearate 0.6 mg 0.3% Colloidal silicone dioxide 0.3 mg 0.2% Total 174.9 mg 100.0% -
-
First pulse-release component THC 0.5 mg 0.3% CBN 5.0 mg 2.5% Microcrystalline Cellulose 135.0 mg 67.8% Hydroxypropylmethylcellulose 41.3 mg 20.8% Croscarmellose Sodium 16 mg 8.0% Magnesium stearate 1.2 mg 0.6% Total 199.0 mg 100.0% Second pulse-release component THC 0.5 mg 0.3% CBN 5.0 mg 2.9% Microcrystalline Cellulose 125.0 mg 71.7% Methacrylic acid copolymer 43.0 mg 24.7% Magnesium stearate 0.6 mg 0.3% Colloidal silicone dioxide 0.3 mg 0.2% Total 174.4 mg 100.0% -
-
First pulse-release component THC 1.0 mg 0.5% CBN 10.0 mg 4.9% Microcrystalline Cellulose 135.0 mg 66.0% Hydroxypropylmethylcellulose 41.3 mg 20.2% Croscarmellose Sodium 16 mg 7.8% Magnesium stearate 1.2 mg 0.6% Total 204.5 mg 100.0% Second pulse-release component THC 1.0 mg 0.6% CBN 10.0 mg 5.6% Microcrystalline Cellulose 125.0 mg 69.5% Methacrylic acid copolymer 43.0 mg 23.9% Magnesium stearate 0.6 mg 0.3% Colloidal silicone dioxide 0.3 mg 0.2% Total 179.9 mg 100.0% -
-
First pulse-release component THC 2.0 mg 0.9% CBN 20.0 mg 9.3% Microcrystalline Cellulose 135.0 mg 62.6% Hydroxypropylmethylcellulose 41.3 mg 19.2% Croscarmellose Sodium 16 mg 7.4% Magnesium stearate 1.2 mg 0.6% Total 215.5 mg 100.0% Second pulse-release component THC 2.0 mg 1.0% CBN 20.0 mg 10.5% Microcrystalline Cellulose 125.0 mg 65.5% Methacrylic acid copolymer 43.0 mg 22.5% Magnesium stearate 0.6 mg 0.3% Colloidal silicone dioxide 0.3 mg 0.2% Total 190.9 mg 100.0% - This Example describes a method of formulating an example 2-pulse oral dosage form of THC and CBN. For example, example THC and CBN oral dosage forms of Example 1 (e.g., Examples 1a, 1b, 1c, 1d, 1e and 1f, among others described herein) may in some embodiments be formulated according to the methods described in Example 2. In this example, the THC and CBN is formulated in a 50:50 ratio of immediate release (“IR THC+CBN”, for release in pulse 1): extended release (“ER THC+CBN”, for release in pulse 2).
- Dispensing and Raw Material Preparation
- (a) Preparation of Coating Suspension:
- Weigh VIVACOAT Protect E into an appropriately sized container. Weigh 60 mL Ethanol into a suitably sized beaker equipped with a magnetic stir bar. Place beaker with Ethanol onto the magnetic stir plate and begin mixing vigorously without splashing. Slowly add the VIVACOAT Protect E to the Ethanol while stirring. Stir speed may be adjusted as needed.
- (b) Preparation of the Oil Containing the THC and CBN:
- Heat an amount of oil sufficient to contain the desired amount of THC and CBN (e.g., about 30 mL to 120 mL) in an oven at 90° C. to lower the viscosity.
-
- (i) Preparation of ER THC+CBN oil:
- Weigh half of the oil containing THC and CBN into a beaker with a magnetic stir bar—this half of the oil will be the ER THC+CBN oil. Place beaker on magnetic stir plate and begin spinning. Weigh out the Ethanol (approximately 60 mL) and add it to the ER THC+CBN oil. Some stirring with a spatula may be required for the stir bar to spin freely. Adjust speed of the magnetic stirrer to maintain good mixing.
-
- (ii) Preparation of IR THC+CBN oil:
- Move the remaining half of the oil containing THC and CBN to a magnetic stir plate with a stir bar and begin stirring—this half of the oil will be the IR THC+CBN oil. Weigh out the Ethanol (approximately 60 mL) and add it to the IR THC+CBN oil. Some stirring with a spatula may be required for the stir bar to spin freely. Adjust speed of the magnetic stirrer to maintain good mixing.
-
- (c) Preparation of the substrate and microcrystalline cellulose LP200:
- Weigh out a first aliquot of 1,000 g of substrate (e.g., sugar spheres) and load into the bowl of a planetary mixer. Weigh out a second aliquot of 1,000 g of substrate into a separate container and set aside. Weigh a first portion of 600 g of microcrystalline cellulose LP200 into a container. Weigh a second portion of 600 g of microcrystalline cellulose LP200 in a separate container. Weigh a third portion of 400 g of microcrystalline cellulose LP200 in a separate container.
- Plating and Coating
- (a) Preparation of ER THC+CBN Powder:
- Begin mixing the first aliquot of the substrate in the mixer at low speed. Slowly add the ER THC+CBN oil into the substrate while mixing. Maintain a slow consistent pour until all ER THC+CBN oil has been added. Use some extra Ethanol to rinse any residual oil from the beaker and add to the substrate. Slowly add the first portion of microcrystalline cellulose LP200 to the mixer. Stir well until combined, stopping when needed to break up clumps. Ensure all the ER THC+CBN oil is incorporated into substrate and microcrystalline cellulose LP200. Continue slowly mixing and slowly add the VIVACOAT Protect E/Ethanol coating suspension. Maintain a slow consistent pour until all coating suspension has been added. Slowly add the 400 g portion of microcrystalline cellulose LP200 to the mixing bowl while mixing at slow speed. Stir well until combined, stopping when needed to break up clumps. Empty mixer contents onto a baking sheet and spread out for drying.
- (b) Preparation of IR THC+CBN Powder:
- Begin mixing second aliquot of substrate in the mixer at low speed. Slowly add the IR THC+CBN oil into the substrate while mixing. Maintain a slow consistent pour until all the IR THC+CBN oil has been added. Use some extra Ethanol to rinse any residual oil from the beaker and add to the substrate. Slowly add the remaining microcrystalline cellulose LP200 to the mixer. Stir well until combined, stopping when needed to break up clumps. Ensure all the IR THC+CBN oil is incorporated into substrate and microcrystalline cellulose LP200. Empty mixer contents onto a baking sheet and spread out for drying.
- Powder Drying
- Dry the ER and IR powders under high vacuum with no heat for ˜3 hours or until dry. If a vacuum environment is not available, place trays on a baker's rack and set in a low humidity (
RH 45%) room overnight. Retrieve trays with dried powder. Keep ER and IR powders separate until the blending step (below). Break up clumps by hand or with a mortar and pestle. Sieve the powders separately through a #20 mesh screen. If not blending right away, double bag the powders separately and seal with a desiccant pack in the outer bag. - Blending
- Load the ER and IR powder into a V-Blender. Weigh microcrystalline cellulose M302 and add it to the V-Blender. Weigh Isomalt and add it to the V-Blender. Weigh croscarmellose sodium and add it to the V-Blender. Blend the mixture at top speed for 2 minutes. Weigh and sieve blue dye through a #20 mesh screen. Add the blue dye by making a shallow pocket in the center of the powder, adding the blue dye, and filling the pocket with the powder blend. Blend mixture for 12 minutes. Weigh and sieve magnesium stearate through a #20 mesh screen. Add the magnesium stearate to the blend in the same manner as the blue dye. Blend mixture for 2 minutes. Discharge blend slowly into a poly bag. Double bag with desiccant pack in the outer bag.
- Tableting
- Load the powdered blend into the hopper of an Elizabeth EP 200 tablet press. Begin batch compression utilizing the following parameters: tablet tooling 9 mm round concave; tablet hardness 6-20 kp. Compress at the target weight and collect tablets in an appropriately sized container.
- In vitro dissolution testing was performed on a 2-pulse oral dosage form of THC and CBN.
- The in vitro dissolution testing was performed as follows:
- The example pulse-release oral dosage form was placed in 0.1 N HCl for two hours, with sampling time points at 1, 1.5 and 2 hours, followed by 8 hours in sodium phosphate buffer pH 6.8, at 37° C.±0.5° C., with sampling at 3, 3.5, 4, 5, 6, 7, 8, 9 and 10 hours.
- THC concentration was measured using HPLC.
-
FIG. 1 is a graph reporting the in vitro dissolution release rate (g/mL per timepoint) of THC versus time in hours of an example 2-pulse oral pharmaceutical composition tablet. The immediate release component (providing pulse 1) began to be dissolved immediately, resulting in a first time of peak release rate (PRR1) after 1-2 hours. Dissolution of the delayed release component (pulse 2) provided a second time of peak release rate (PRR2) after 3-4 hours. -
FIG. 2 is a graph reporting the dissolution profile of cumulative release of % total THC dose versus time in hours of the example 2-pulse oral pharmaceutical composition tablet. 50% of the total dose of the THC API was released after about 2 hours, and 90% of the total dose of THC API was released after about 5 hours. - Cannabis as a sleep improvement solution has been receiving increased attention, in light of the current legalization of cannabis for medical use in 33 states and Washington D.C. The influence of delta-9 Tetrahydrocannabinol (THC) combined with cannabinol (CBN) on sleep is preliminary, but pre-clinical research indicates that CBN may prolong sleep and be particularly effective when combined with other cannabinoids (Yoshida et al., 1995; Russo, 2011). The aim of the study in this Example was to evaluate the impact of a combination of 10 mg THC and 5 mg CBN in a pulse-release tablet on the ability for participants (medical cannabis users) to stay asleep. The effect of the combination tablet was evaluated using objectively measured and self-reported data.
- SleepScore Max® (Consumer Sleep Solutions LLC, Delaware) was used to measure objective sleep, and self-report questionnaires were used to measure perceived sleep. The SleepScore Max® device uses Ultra-Wideband Technology to track the subject's bodily gross and micro movements. SleepScore Max®, is a validated non-contact monitor designed to unobtrusively and objectively measure sleep at the user's home.
- Objective data demonstrated that before using the combination tablet, participants slept 6 hours and 29 minutes on average, whereas during the combination tablet use period participants slept 20 minutes longer (6 hours and 49 minutes) on average (p<0.001; 5% improvement). Participants reported a 22% improvement in feeling well-rested in the morning (p<0.0001), with an average rating of 53.32 before product use and a rating of 65.21 during product use. Finally, participants reported an 18% increase in overall sleep quality (p<0.0001), going from an average of 57.36 before product use to 67.90 during product use.
- This validation study found that the example dosage form combining THC with CBN was associated with improved sleep in a sample of medical cannabis users. This was demonstrated using both objective sleep data using validated SleepScore® (Consumer Sleep Solutions LLC, Delaware) technology, and self-reported data.
- The cultivation and use of the cannabis plant for its medicinal and industrial benefits date back to ancient times. The use of cannabis as a method to improve sleep has been receiving increased attention, in light of the current legalization of cannabis for medical use in 33 states and Washington D.C. (NCSL, 2020). Recent studies indicate that individuals using cannabis expect it to decrease their sleep-related problems (Altman et al., 2019) and are likely to reduce their use of sleep medications (Piper et al., 2017). Participants in the study by Altman and colleagues (2019) reported that using cannabis helped them fall asleep about 15 minutes faster and sleep for about 2 hours longer. However, further research is needed to understand the objective and perceived effects of cannabinoids on sleep.
- Delta-9 tetrahydrocannabinol (THC) is one of the most widely studied cannabinoids, but reviews of the scientific literature (Gates et al., 2014; Babson et al., 2017) document that its effects on sleep are not yet well understood. An early study by Cousens and DiMascio (1973) found that THC decreased time to fall asleep, measured objectively, but led to a “hangover” after-effect (i.e., continued effects, e.g. a continued “high” the following day). However, Chait (1990) found that THC was not associated with hangover effects. Other early studies suggested that THC might reduce REM sleep duration (Pivik et al., 1972; Feinberg et al., 1975) and increase deep sleep duration (Pivik et al., 1972; Barratt et al., 1974).
- Recent research has benefited from a more sophisticated understanding of THC and sleep relative to earlier eras. Nonetheless, the optimal concentration, dosage, timing, and route of administration remain unknown (Babson et al., 2017). Given these complexities and more, it has been noted in the scientific literature that laboratory studies do not reflect people's naturalistic experiences of cannabis use and sleep (Bowles et al., 2017). The current study categorized sleep into four commonly known stages including light sleep, deep sleep, rapid eye movement (REM), and wake.
- Materials and Methods
- Participants
- Curio Wellness, LLC recruited medical cannabis patients, certified by the Maryland Medical Cannabis Commission, who self-identified as experiencing insomnia, in particular the subjects in this study felt they had trouble staying asleep. Eligible participants were asked to visit Curio Wellness dispensary in person on two occasions. During the second visit, they picked up the cannabis pulse-release dosage and reviewed the study instructions.
- Forty-one people who met all eligibility criteria were recruited for participation. All participants signed an informed consent form prior to beginning the study, informing them of potential risks and benefits as well as other information about the voluntary study. Participants were given a $100 gift card upon completion of the study.
- Design
- A non-counterbalanced, pre-post study design was used. A placebo-controlled trial was preferred, however due to the State of Maryland labeling requirements for medical cannabis products, this was not possible. Instead, the investigators decided a pre-product use period to establish sleep performance using SleepScore® would establish a baseline for comparison when treated with the pulse-release dosage form. Both quantitative and qualitative self-report data, as well as objective sleep data, were collected. During the first visit, study participants reviewed and signed informed consent, picked up the SleepScore Max® device, downloaded the research version of the SleepScore Max® companion app, and reviewed the study instructions. The product was tested in-home, giving the advantage of providing insight into the effectiveness of the product under real-life conditions and hence yielding more ecologically valid results.
- An overview of the timeline is displayed in
FIG. 3 . The pre-product use period consisted of 3 weeks during which participants were instructed to track their sleep every night using SleepScore Max and complete a brief daily questionnaire each morning. During this period, participants had not yet received the test product. The product use period consisted of 3 weeks during which participants were asked to use the test product every night, track their sleep with SleepScore Max every night, and complete a brief daily questionnaire each morning. In addition to the brief daily questionnaires that were sent each morning, participants were asked to complete three more in-depth sleep experience questionnaires. The first of these sleep experience questionnaires was completed prior to product use, the second was completed after 1 week of product use, and the third was completed at the end of the study (after 3 weeks of product use). - Each study tablet contained 15 mg of total cannabinoids (10 mg of THC+5 mg of CBN). These specific concentrations are commercially available to medical cannabis users in Maryland and were chosen for the current study based on previous research conducted by Curio Wellness. Tablets were a pulse-release dosage form as described in Example 1(a).
- Participants were instructed to swallow the tablet up to 30 minutes before bed, every night for 3 weeks. Participants were also asked to discontinue use of any other
medical cannabis products 3 hours before going to bed, and to stop eating at least 2 hours before bed, during the 3 weeks of the product use period. - Objective sleep data were collected using a SleepScore Max® system, a non-contact monitor designed to unobtrusively and objectively measure sleep at the user's home. SleepScore Max® provides standard annotated 30 second epoch sleep stage data and commonly used sleep metrics such as time to fall asleep (sleep onset latency), number of awakenings, start and end of sleep sessions, and total sleep time. Time spent in light sleep, deep sleep, and REM sleep (e.g. in minutes) together add up to total sleep time. Wake after sleep onset describes the total number of minutes a person is awake after falling asleep for the first time and before waking up prior to getting up. The total time in bed describes the time between getting in and out of bed (from “lights out, start tracking session” to “lights on, stop tracking session” according to the SleepScore Max® app). With these measures, sleep efficiency and sleep maintenance can be calculated. Sleep efficiency (in %) is calculated by dividing total sleep time by time in bed. Sleep efficiency of 85% and higher is considered to reflect good sleep quality (Ohayon et al., 2017). Sleep maintenance (in %) describes the ability of staying asleep once asleep, taking into account waking up too early (before getting out of bed) and/or struggling to get back to sleep (but not the time it takes to fall asleep initially) and is calculated by dividing total sleep time by the sum of the duration of all sleep stages, including wake, after initially falling asleep. Also, all four relative stage durations (% Light, % Deep, % REM, and % Wake) were calculated by dividing stage duration by the sum of the duration of all sleep stages, including wake, after initially falling asleep.
- Validity of these sleep measurements has been shown multiple times, with good performance compared to the gold standard sleep measurement technique of polysomnography (O'Hare et al., 2014; Zaffaroni et al., 2017; Schade et al., 2019; Zaffaroni et al., 2019). The SleepScore® technology can be compared to ultra-low energy radar. The sensitivity of the sensor and the performance of the signal processing algorithms allow the detection of gross body movement and full respiration patterns by measuring the micro motion of the chest cavity.
- SleepScore Max® provided three sleep scores: SleepScore®, Body Score, and Mind Score. These are normalized 100-point sleep quality scales, based on proprietary algorithms, using scientific averages for a user's age and gender (Ohayon et al., 2004). SleepScore® is defined by six sleep parameters (total sleep duration, time to fall asleep, time in light sleep, time in deep sleep, time in REM, and number of awakenings throughout the night) and can be regarded as a general sleep quality scale. Mind Score reflects the amount of REM sleep, which is known to play an important role in creative thinking, problem solving, and emotional processing. Body Score reflects the amount of deep sleep, which is considered restorative sleep and is linked to the perception of feeling well-rested the next day.
- Participants used the research version of the SleepScore Max® companion app, called Max R. Max R is a slimmed down version of the publicly available SleepScore Max® app, dedicated to serve as a sleep recording device, and available for researchers at request. Max R sleep recorder tracks sleep in the same way as the publicly available app, but it does not display sleep data and does not offer consumer features such as the sleep guide or smart alarm. It simply acts as a sleep tracker.
- Brief daily questionnaires were sent each morning using Survey Monkey to check compliance with sleep tracking, check compliance with use of the pulse-release dosage during the product use period, and measure perceived sleep (e.g., “How long did you feel it took to fall asleep last night?”). These brief daily questionnaires were administered during the entire 6-week study, both before and during product use.
- Nightly objective sleep data and daily self-report data were analyzed in R (version 3.5.2) using multilevel regression analyses, taking into account the nested structure of the data (nights within subjects). An alpha level of 0.05 was used. For the objective sleep data, analyses compared nights in the pre-product use period on which participants tracked their sleep to nights in the product use period on which participants tracked their sleep and reported using the test product. For the daily self-report data, analyses compared nights in the pre-product use period on which participants provided responses to nights in the product use period on which participants provided responses and reported using the test product.
- MS Excel (version 1901, for Windows) was used to analyze the quantitative self-report sleep data from the sleep experience questionnaires. Descriptive statistics and one-tailed, paired-samples t-tests were conducted, using an alpha level of 0.05. Analyses compared responses to the sleep experience questionnaire administered before product use to the subsequent sleep experience questionnaires.
- Results
- Of the 41 participants who were recruited into the study, 1 did not register a SleepScore Max® account and 2 chose to withdraw. Of those who withdrew from the study, one cited a preexisting medical condition and the other experienced technological difficulties. In addition, a few individuals remained in the study but did not provide complete data. Therefore, due to missing SleepScore Max® data, the objective sleep analyses included 35 participants. Similarly, due to missing survey data, the perceived sleep analyses included self-report data from 35 participants.
- Demographics
- The average age of study participants was 47, ranging from 22 to 69. The sample was 57% female. Over three-quarters (77%) described their race as White, and over half (54%) were married. The majority (57%) were working full-time, and 63% had finished college or earned graduate degrees. Annual household income ranged from less than $20,000 (3%) to $100,000 or higher (40%).
- At the beginning of the study, the most common medical conditions for which participants reported using cannabis were sleep/insomnia (69%), pain (40%), and generalized anxiety disorder (29%). Full results summarizing the medical conditions for which participants reported using cannabis are shown in
FIG. 4 . - Participants' sleep concerns during the weeks before product use are shown in
FIG. 5 . The most common answer (83%) was waking up too often in the night, followed by not feeling well rested when waking up in the morning (74%). In addition, about one quarter (26%) reported taking too long to fall asleep and waking up too early in the morning. The finding that concerns about being able to stay asleep during the night outweighed concerns about being able to fall asleep confirms that the participants who were recruited for the current study were an appropriate match for the product being tested. - Participants were asked whether medical cannabis made them feel sleepy; 89% replied yes and 11% replied no. They reported using a variety of forms of cannabis in the past to help with sleep. The most common form used was flower (49%). Full results summarizing forms of cannabis study participants had used in the past to help with sleep are shown in
FIG. 6 . - Results of the objective sleep analyses are shown in Table 1. These results revealed that treatment effects on parameters of wake after sleep onset, number of awakenings, sleep efficiency, and sleep maintenance were not significant. Nor was there a significant change in time to fall asleep. However, participants' average length of time in bed increased by 22 minutes (p<0.001; 5% improvement), leading to a healthier amount of sleep. Before using the test product, study participants slept 6 hours and 29 minutes on average, whereas during the product use period they slept 20 minutes longer (6 hours and 49 minutes) on average (p<0.001; 5% improvement). This increase in total sleep time translated into more light sleep, both in duration (p<0.001; 7% increase) and proportion of time (p=0.02). Taken together, these changes indicate improved sleep, reflected in a significant increase in SleepScore. Prior to using the test product, participants had an average SleepScore of 78.98. While using the test product, average SleepScore rose to 80.21 (p=0.03; 2% increase), which is similar to the average SleepScore for SleepScore Max® users in the same age group as the study sample. Objective sleep and multilevel regression results comparing nights before product use to nights during product use for n=35 (n=1020 nights) are presented in Table 1.
-
TABLE 1 Objective Sleep Analyses Sleep Score: Baseline Treatment Effect vs. Baseline. Observed Pre-test Period Prod- Estimated (Base- uct Con- p- line) Use stant beta value SleepScore (0-100) 78.98 80.21 79.04 1.232 0.033 BodyScore (0-100) 76.50 76.66 76.50 0.081 0.451 MindScore (0-100) 78.18 79.87 78.26 1.479 0.055 Total Sleep 388.91 408.96 389.30 20.719 <0.001 Time (minutes) Sleep Onset 21.58 24.94 21.58 2.655 0.051 Latency (minutes) Number of Awakenings 4.78 4.94 4.78 0.214 0.069 Wake After Sleep 43.43 44.36 43.57 1.506 0.225 Onset (minutes) Time in Bed (minutes) 460.35 482.22 460.66 22.917 <0.001 Sleep Efficiency 84.26 83.76 84.22 −0.396 0.256 Sleep Maintenance 84.43 84.41 84.40 −0.154 0.396 Light (minutes) 240.49 256.36 240.75 17.003 <0.001 REM (minutes) 76.58 79.74 76.79 2.474 0.096 Deep (minutes) 71.84 72.86 71.76 1.170 0.241 % Light sleep 55% 56% 55% 0.983 0.018 % REM sleep 18% 17% 18% −0.276 0.234 % Deep sleep 17% 17% 17% −0.610 0.067 % Wake after sleep onset 10% 10% 10% −0.106 0.399 - For pre-test period and the product use period, each average was calculated by averaging nights across participants, and then averaging those participants' averages to a single simple average, listed under “Observed” in the Table 1. Listed under “Estimated” in Table 1 are the outcomes of the multilevel regression analyses. Regression model was as follows: Sleepmeasureij=Const0ij+B*TestPeriodij; TestPeriod coded as 0 for the observations during nights when participants were not using the pulse-release dosage, and 1 for nights when participants tracked their sleep and reported using the pulse-release dosage. Nights during the product use period in which participants did not have objective data or did not report using the pulse-release dosage were not included in analyses.
- Analyses of the daily self-report data suggested that the pulse-release dosage helped participants experience better sleep. Analyses of the daily self-report data suggested that the test product helped participants experience better sleep. Participants perceived fewer nighttime awakenings after falling asleep, going from 2.87 before product use to 2.33 during product use (p<0.0001; 19% decrease). They also reported getting out of bed fewer times, from 1.21 before product use to 0.95 during product use (p<0.0001; 21% decrease). In addition, participants reported a 22% improvement in feeling well-rested in the morning (p<0.0001), with an average rating of 53.32 before product use and a rating of 65.21 during product use. Participants reported a 18% increase in overall sleep quality (p<0.0001), going from an average of 57.36 before product use to 67.90 during product use. See Table 2.
-
TABLE 2 Self-report daily questionnaire and multilevel regression results comparing nights before product use to nights during product use for n = 35 (n = 1236 nights). Observed Pre- Prod- Estimated test uct Con- p- Period Use stant beta value Bedtime Sleepiness (0-100) 65.71 67.02 65.74 1.293 0.103 Time to Fall Asleep (minutes) 24.58 24.25 24.37 0.059 0.482 Number of Awakenings 2.87 2.33 2.86 −0.531 <0.0001 Number of Times Out of Bed 1.21 0.95 1.21 −0.256 <0.0001 Well-rested in the 53.32 65.21 53.38 11.922 <0.0001 Morning (0-100) Sleep Quality (0-100) 57.36 67.90 57.43 10.59 <0.0001 - For pre-test period and the product use period, each average was calculated by averaging nights across participants, and then averaging those participants' averages to a single simple average, listed under “Observed” in Table 2.
- Overall, study participants reported feeling more satisfied with their sleep and felt better in the morning. Before using the product, they woke up feeling rested only 2 mornings per week. By the end of the study, this had increased to 4 mornings per week. They reported napping less often during the day, presumably because they were sleeping much better at night. These effects all were shown after 1 week of using the product and were sustained through the end of the study (3 weeks of product use).
- The results of the daily questionnaires were confirmed by significant sleep improvements that were observed when comparing the sleep experience questionnaires. The first of these sleep experience questionnaires was completed before the product use period, the second was completed after 1 week of product use, and the third was completed at the end of the study (after 3 weeks of product use). First, to test for a 1-week effect, we compared participants' perceptions of their sleep after 1 week of using the product to how they perceived their sleep before using the product. Significant improvements were found for number of awakenings, time awake during the night after falling asleep, total sleep time, feeling well-rested in the morning, overall sleep satisfaction, and frequency of daytime napping. Next, to test for a 3-week effect, participants' perceptions of their sleep at the end of the study were compared to how they perceived their sleep before using the product. All significant effects noted at 1 week were sustained at 3 weeks: number of awakenings, time awake during the night after falling asleep, total sleep time, feeling well-rested in the morning, overall sleep satisfaction, and frequency of daytime napping. Details are presented in
FIG. 7 toFIG. 12 . - As shown in
FIG. 7 , participants felt they woke up less often during the product use period. Before using the product, they reported waking up 3 times per night on average. This decreased to 2 times per night after 1 week of using the product (p=0.009) and stayed at 2 times per night after 3 weeks of using the product (p=0.007). As shown inFIG. 8 , participants felt they spent less time awake at night (after falling asleep initially) during the product use period. There was a 26-minute decrease in perceived amount of time awake after 1 week of using the product (p=0.005). After 3 weeks of product use, there was a 14-minute decrease compared to when participants were not using the product (p=0.03). As shown inFIG. 9 , participants felt they slept more during the product use period. There was a 37-minute increase in perceived nightly total sleep time after 1 week of using the product (p<0.001). After 3 weeks of product use, there was a 35-minute increase compared to when participants were not using the product (p<0.001). As shown inFIG. 10 , participants felt more well rested upon waking in the morning during the product use period. Before using the product, they woke up feeling rested only 2 mornings per week. This increased to 3 mornings per week after 1 week of product use (p<0.001) and 4 mornings per week after 3 weeks of product use (p<0.001). As shown inFIG. 11 , participants were more satisfied with their sleep during the product use period. Before using the product, they reported feeling satisfied 3 nights per week. This increased to 4 nights per week after 1 week of product use (p=0.003) and remained at 4 nights per week after 3 weeks of product use (p=0.004). As shown inFIG. 12 , participants reduced their frequency of taking daytime naps during the product use period. Before using the product, they reported napping 3 days per week. This decreased to only 1 day per week after 1 week of product use (p<0.001) and continued to be only 1 day per week after 3 weeks of product use (p<0.001). Due to the State of Maryland labeling requirements for medical cannabis products, a placebo controlled trial was not possible regarding the conduct of this study. - The timing of this study unexpectedly coincided with the COVID-19 pandemic. Given that the study design did not include a control group, the extent to which the effects were caused by the cannabis pulse-release dosage versus health and lifestyle changes associated with the COVID-19 pandemic cannot be fully known. Data collection occurred from February 24 to April 5. Maryland's stay-at-home directive was not ordered until Mar. 30, 2020 (Wenger & Wood, 2020), but closures of non-essential business, school closings, and other restrictions began earlier (Dance, 2020). The increase in total sleep time found in the current study sample is in the same direction as national SleepScore® data from Mar. 16-Apr. 3, 2020, showing that, on average, people in the United States spent more time in bed and slept longer during COVID-19 restrictions compared to before (SleepScore Labs, 2020).
- In summary, the validation study in this Example evaluated the effectiveness of a pulse-release oral dosage form product combining THC with CBN to improve ability to stay asleep. Medical cannabis patients certified by the Maryland Medical Cannabis Commission who felt they had trouble staying asleep were recruited by Curio Wellness into the study. The research participants tracked their sleep for 3 weeks and then tested the product for 3 weeks in their own homes while continuing to track their sleep. This way of testing has the advantage of providing insight into the effectiveness of the product under real-life conditions and hence yielding more ecologically valid results.
- The tablets were administered as a pulse-release dosage form: the dosage form was designed so that half of the dosage was released immediately after oral administration, and the remaining half was released 2-3 hours later. The study in this Example found that an example product combining THC with CBN was directly associated with both improved objective and perceived sleep quality and duration in a sample of medical cannabis users.
- This Example describes a study evaluating the impact of a combination of 10 mg THC and 5 mg CBN in an immediate-release sublingual tablet on the ability for participants (medical cannabis users) to fall asleep. The effect of the combination tablet was evaluated using objectively measured and self-reported data.
- The combination cannabinoid tablet was tested in 28 medical cannabis patients certified by the Maryland Medical Cannabis Commission who felt they had trouble falling asleep, covering 445 nights of use of the product.
- Analysis of the objective sleep data indicated that use of the falling asleep tablet was unexpectedly associated with a statistically significant increase in how long it took to fall asleep. Participants' average sleep onset latency slightly rose from 24 minutes without intervention to 26 minutes when using the falling asleep tablet. In addition to the effect on falling asleep, the objective sleep data also showed small but significant declines in sleep efficiency (−1%) and sleep maintenance (−1%), both outcome measures reflecting the ability to spend time in bed asleep rather than awake.
- Mirroring the objective data, the self-report data did not show improvement in how many minutes participants felt it took them to fall asleep. Perceived sleep onset did not change significantly across the daily questionnaires or the three sleep experience questionnaires. However, there was significant improvement in how often participants felt that they fell asleep within their preferred amount of time, going from an average of 3 nights per week to 4 nights per week.
- Despite the lack of improvement in falling asleep faster, participants reported that the product helped their sleep in many other ways. At the end of the study, they felt sleepier at bedtime, felt more rested in the morning, and were more satisfied with their sleep, compared to the weeks before using the test product. They also felt they woke up less often and got out of bed less often during the night. In addition, participants reported a significant decrease in how often feelings of sleepiness affected their school, work, or private life.
- Materials and Methods
- Participants
- Curio Wellness recruited medical cannabis patients, certified by the Maryland Medical Cannabis Commission, who self-identified as experiencing insomnia, in particular the subjects in this study felt they had trouble falling asleep. Curio Wellness obtained informed consent from all participants and provided them with the cannabis test product, a SleepScore Max® device, a guide for using the research version of the SleepScore Max® companion app, and additional study instructions.
- To be considered for participation, the medical cannabis patients had to be at least 21 years old and willing to track their sleep every night for 6 weeks. They also had to be willing to use the test product every night for 3 weeks, and willing to discontinue other cannabis use at least 3 hours before bed during the product use period.
- In order to test the product in a sample of otherwise healthy users, people with other sleep disorders (e.g., narcolepsy, restless leg syndrome, sleep apnea) or psychological disorders affecting sleep (e.g., clinical depression, bipolar disorder, schizophrenia) were excluded. People taking sleep medications (prescription or over-the-counter) or anti-convulsant medications were excluded, as were people who typically had 3 or more alcoholic beverages on 4 or more nights per week. Women who were pregnant, lactating, or planning to become pregnant in the next 2 months were excluded. Other exclusion criteria included being a shift worker, having a child at home under 12 months old, or planning to travel across multiple time zones or be away from home for more than 5 days during the entire study.
- 35 people who met all eligibility criteria were recruited for participation. All participants signed an informed consent form prior to beginning the study, informing them of potential risks and benefits as well as other information about the voluntary study. Participants were given a $100 gift card upon completion of the study.
- Study Design
- A non-counterbalanced, pre-post study design was implemented. Participants were aware of the sleep benefit of the intervention. Both quantitative and qualitative self-report data, as well as objective sleep data, were collected. The data collection period of the study was executed from March 23-May 3, 2020. The product was tested in-home, giving the advantage of providing insight into the effectiveness of the product under real-life conditions and hence yielding more ecologically valid results. An overview of the timeline is displayed in
FIG. 13 - The pre-product use period consisted of 3 weeks during which participants were instructed to track their sleep every night using SleepScore Max® and complete a brief daily questionnaire each morning. During this period, participants had not yet received the test product.
- The product use period consisted of 3 weeks during which participants were asked to use the test product every night, track their sleep with SleepScore Max® sleep measurement system every night, and complete a brief daily questionnaire each morning.
- In addition to the brief daily questionnaires that were sent each morning, participants were asked to complete 3 longer surveys. The first of these sleep experience questionnaires was completed prior to product use, the second was completed after 1 week of product use, and the third was completed at the end of the study (after 3 weeks of product use).
- Procedures
- Participants were provided with instructions on how to set up and use SleepScore Max® and the companion app. Detailed instructions for using the test product were reviewed with each participant by a Curio Wellness study staff member. Participants were asked to discontinue use of any other
medical cannabis products 3 hours before going to bed, and to stop eating at least 2 hours before bed, during the 3 weeks of the product use period. They were instructed to take 1tablet 15 to 30 minutes before bed, every night for 3 weeks. - Cannabis Test Product
- Each tablet contained 15 mg of total cannabinoids (10 mg of THC+5 mg of CBN). These specific concentrations are commercially available to medical cannabis users in Maryland and were chosen for the current study based on previous research conducted by Curio Wellness. The tablet form was dissolvable immediate release, and the delivery method was sublingual.
- Measures
- For this study, both objective and self-report sleep data were collected.
- Sleep Tracking
- Objective sleep data were collected using SleepScore Max® as described in Example 4.
- Questionnaires
- Self-report data were collected as described in Example 4.
- Data Analyses
- Data analyses were performed as described in Example 4.
- Results
- Of the 35 individuals who were recruited into the study, one withdrew due to illness. Another participant reported technological difficulties, and some remained in the study but did not provide complete data. Therefore, due to missing SleepScore Max® data, the objective sleep analyses included 28 participants. Similarly, due to missing survey data, the perceived sleep analyses included self-report data from 26 participants.
- The 28 participants who consistently tracked their sleep did so for 79% of all nights in the study. There were 481 nights of tracked sleep before test product use and 445 nights during which participants used the test product and tracked their sleep (76% compliance rate for both activities during product use).
- Across the sample of 28 participants who consistently provided daily self-report data, there were 982 daily questionnaire responses (84% response rate). Participants reported using the test product for 86% of nights during the product use period (but did not track their sleep on all of those nights). For the nights participants reported not using the test product, they stated reasons such as not sleeping at home that night, worry about not waking up on time the next morning, and having a cold. No one reported taking more than the recommended dose.
- According to SleepScore Max® user registration data, the average age was 41, ranging from 24 to 71. Based on data collected in the first sleep experience questionnaire, 65% were female, 84% described their race as White, and over half (54%) were married. The majority (53%) were working full-time, and 43% had finished college or earned graduate degrees. Annual household income ranged from less than $20,000 (4%) to $100,000 or higher (34%).
- At the beginning of the study, the most common medical conditions for which participants reported using cannabis were insomnia (73%), generalized anxiety disorder (50%), and pain (31%). Full results are shown in
FIG. 14 . - The most common sleep concern during the weeks before starting to use the falling asleep tablet was taking too long to fall asleep (92%), followed by not feeling well rested when waking up (85%) or throughout the day (77%). Full results are shown in
FIG. 15 . The finding that concerns about falling asleep outweighed other types of sleep concerns confirms that the participants who were recruited for the current study were an appropriate match for the product being tested according to their self-report. - Participants were asked whether medical cannabis made them feel sleepy; 81% replied yes and 19% replied no. They reported using a variety of forms of cannabis in the past to help with sleep. The most common form used was flower (69%). Full results are shown in
FIG. 16 . - Sleep Measured Objectively
- Participants were recruited into the study based on self-reported difficulty falling asleep. Before product use, participants reported taking 37.50 minutes to fall asleep on average. However, objective sleep data collected before product use showed that they actually fell asleep in 23.56 minutes on average. This length of sleep onset time is longer than the average for SleepScore Max® users in the same age group as the study sample (20.58 minutes) but still within the range considered to be normal in the scientific and clinical sleep literature (less than 30 minutes; Edinger et al., 2004; Ohayon et al., 2017). In the current sample, during the period before using the product, on only 22% of nights did the participants take 30 or more minutes to fall asleep.
- Therefore, it appears that there may have been little room for improvement in objective sleep onset in this sample.
- Analysis of the objective sleep data indicated that the test product was unexpectedly associated with a statistically significant increase in how long it took to fall asleep (p=0.021). Before using the test product, as noted above, participants had an average sleep onset latency of 23.56 minutes. This average rose to 26.40 minutes during product use (12.05% increase). Related to the increased onset latency, a statistically significant decrease in sleep efficiency during the product use period (p=0.029) going from 84.39% before product use to 83.34% during product use (1.24% relative decrease) was observed. Similarly, sleep maintenance decreased (p=0.047), going from 84.50% before product use to 83.64% during product use (1.02% relative decrease). Taken together, these changes indicate that participants had a harder time falling asleep and staying asleep. See Table 3.
-
TABLE 3 Objective sleep and multilevel regression results comparing nights before product use to nights during product use for n = 28 (n = 926 nights). Observed Pre- Prod- Estimated test uct Con- p- Period Use stant beta value SleepScore (0-100) 77.96 77.32 77.99 −0.552 0.190 BodyScore (0-100) 75.74 76.03 75.73 0.419 0.272 MindScore (0-100) 77.40 77.17 77.45 0.067 0.469 Total Sleep Time (minutes) 400.60 393.74 400.85 −5.520 0.101 Sleep Onset 23.56 26.40 23.64 2.748 0.021 Latency (minutes) Number of Awakenings 4.86 4.92 4.87 0.038 0.396 Wake After Sleep 45.03 46.85 44.88 1.903 0.175 Onset (minutes) Time in Bed (minutes) 475.24 473.31 475.29 −0.077 0.493 Sleep Efficiency 84.39 83.34 84.34 −0.887 0.029 Sleep Maintenance 84.50 83.64 84.47 −0.773 0.047 Light (minutes) 250.11 246.71 250.28 −2.883 0.202 REM (minutes) 77.50 74.69 77.71 −2.503 0.086 Deep (minutes) 72.99 72.34 72.86 −0.072 0.483 % Light Sleep 56% 55% 56% −0.192 0.342 % REM Sleep 17% 17% 17% −0.466 0.100 % Deep Sleep 17% 17% 17% 0.110 0.393 % Wake After Sleep Onset 10% 11% 10% 0.541 0.091 - In Table 3, for pre-test period and the product use period, each average was calculated by averaging nights across participants, and then averaging those participants' averages to a single simple average, listed under “Observed” in Table 3. Listed under “Estimated” are the outcomes of the multilevel regression analyses. Regression model was as follows: Sleepmeasureij=Const0ij+B*TestPeriodij; TestPeriod coded as 0 for the observations during nights when participants were not using the test product, and 1 for nights when participants tracked their sleep and reported using the test product. Nights during the product use period in which participants did not have objective data or did not report using the test product were not included in analyses.
- Given these surprising results, additional analyses were performed to test whether effects would be observed in specific subgroups. An analysis was conducted to determine whether objective sleep improvement occurred in the subgroup of participants who began the study with the poorest sleep onset latency (objectively measured, above the sample median of 19.80; n=14). This subgroup had the most need for a product that could help them fall asleep faster and the most room for improvement. However, the results were not significant. Another set of analyses was performed with males and females separately. No sleep improvement was found for men or for women.
- Sleep Measured by Daily Self-Report
- Analyses of the daily self-report data found that the test product helped participants feel that they experienced better sleep. Participants felt sleepier at bedtime, going from 59.73 before product use to 65.93 during product use on a 0-100 scale (p<0.001; 10.38% increase). They perceived fewer nighttime awakenings after falling asleep, going from 2.95 before product use to 2.27 during product use (p<0.001; 23.05% decrease). They also reported getting out of bed fewer times, from 1.13 before product use to 0.97 during product use (p=0.01; 14.16% decrease). In addition, participants reported a 23.19% improvement in feeling well-rested in the morning (p<0.001), with an average rating of 49.60 before product use and a rating of 61.10 during product use on a 0-100 scale. Finally, participants reported a 18.31% increase in overall sleep quality (p<0.001), going from an average of 54.30 before product use to 64.24 during product use on a 0-100 scale. However, there was no significant change for daily self-reported sleep onset. See Table 4.
-
TABLE 4 Self-report daily questionnaire and multilevel regression results comparing nights before product use to nights during product use for n = 28 (n = 982 nights). Observed Pre- Prod- Estimated test uct Con- p- Period Use stant beta value Bedtime Sleepiness (0-100) 59.73 65.93 60.02 5.684 <0.001 Sleep Onset 33.51 32.98 33.25 −0.137 0.472 Latency (minutes) Number of Awakenings 2.95 2.27 2.90 −0.621 <0.001 Number of Times Out of Bed 1.13 0.97 1.11 −0.133 0.010 Well-rested in the 49.60 61.10 49.91 11.095 <0.001 Morning (0-100) Sleep Quality (0-100) 54.30 64.24 54.79 9.044 <0.001 - In Table 4, for pre-test period and the product use period, each average was calculated by averaging nights across participants, and then averaging those participants' averages to a single simple average, listed under “Observed” in Table 4. Listed under “Estimated” are the outcomes of the multilevel regression analyses. Regression model was as follows: Sleepmeasureij=Const0ij+B*TestPeriodij; TestPeriod coded as 0 for the observations during nights when participants were not using the test product, and 1 for nights when participants reported using the test product. Nights during the product use period in which participants did not report using the product were not included in analyses.
- Sleep Measured by Sleep Experience Questionnaires
- The results of the daily questionnaires were confirmed by significant sleep improvements that were observed when comparing the sleep experience questionnaires. The first of these sleep experience questionnaires was completed before the product use period, the second was completed after 1 week of product use, and the third was completed at the end of the study (after 3 weeks of product use).
- First, to test for a 1-week effect, we compared participants' perceptions after 1 week of using the product to the time before using the product. There was a significant reduction in how many days feeling sleepy or tired affected school, work, or private life (see
FIG. 17 . No significant changes were found for how many minutes it took to fall asleep or other aspects of perceived sleep. - Next, to test for a 3-week effect, participants' perceptions at the end of the study were compared to the time before using the product. Similar to the aforementioned 1-week effect, there was a reduction in how many days feeling sleepy or tired affected participants' school, work, or private life (see
FIG. 17 ). Participants reported improvements in sleepiness at bedtime (FIG. 18 ) and how many days per week they were able to fall asleep in their preferred amount of time (seeFIG. 19 ), even though there was no significant change in how many minutes on average they reported it took to fall asleep (FIG. 20 ). In addition, there were significant improvements in feeling rested upon waking in the morning (seeFIG. 21 ) and feeling satisfied with sleep (FIG. 22 ). - Discussion
- This validation study evaluated the effectiveness of a product combining THC with CBN to help with falling asleep. Medical cannabis patients certified by the Maryland Medical Cannabis Commission who felt they had trouble falling asleep were recruited by Curio Wellness into the study. The research participants tracked their sleep for 3 weeks and then tested the product for 3 weeks in their own homes while continuing to track their sleep. This way of testing has the advantage of providing insight into the effectiveness of the product under real-life conditions and hence yielding more ecologically valid results.
- SleepScore Max® was used to measure objective sleep, and self-report questionnaires were used to measure perceived sleep. In addition to brief daily questionnaires that were sent each morning of the study to measure compliance and sleep experiences, participants completed 3 longer surveys assessing perceived sleep and user experiences.
- Across the 28 participants with consistent objective sleep data, there were 481 nights of tracked sleep before test product use and 445 nights during which they tracked their sleep and reported using the test product (overall, 76% compliance rate for both activities during product use).
- Participants were recruited into the study based on self-reported difficulty falling asleep. Before using the product, they reported taking 38 minutes to fall asleep on average. However, objective sleep data collected before product use showed that they actually were taking only 24 minutes to fall asleep on average. Taking less than 30 minutes to fall asleep is considered normal in the scientific and clinical sleep literature (Edinger et al., 2004; Ohayon et al., 2017). In the current sample, during the period before using the product, on only 22% of nights did the participants take 30 or more minutes to fall asleep. Therefore, it appears that there may have been little room for improvement in objective sleep onset in this sample.
- Analysis of the objective sleep data indicated that the test product was unexpectedly associated with a statistically significant increase in how long it took to fall asleep. Participants' average onset time rose from 24 minutes before product use to 26 minutes during product use. The objective data also revealed that taking longer to fall asleep impacted sleep efficiency, meaning that participants spent less time asleep while they were in bed. Also, their ability to stay asleep was slightly negatively affected, as indicated by a decrease in sleep maintenance.
- Mirroring the objective data, the self-report data did not show statistically significant improvement in how many minutes participants felt it took them to fall asleep. Perceived sleep onset did not change significantly across the daily questionnaires or the three sleep experience questionnaires. However, at the end of the study there was significant improvement in how often participants felt that they fell asleep within their preferred amount of time, going from an average of 3 nights per week to 4 nights per week.
- Despite the lack of improvement in falling asleep faster, participants reported that the product helped their sleep in many other ways. At the end of the study, they felt sleepier at bedtime, felt more rested in the morning, and were more satisfied with their sleep, compared to the weeks before using the test product. They also felt they woke up less often and got out of bed less often during the night. In addition, participants reported a significant decrease in how often feelings of sleepiness affected their school, work, or private life.
- When interpreting the study results, it must be considered that the timing of this study unexpectedly coincided with the COVID-19 pandemic. Given that the study design did not include a control group, the extent to which the effects were caused by the cannabis test product versus health and lifestyle changes associated with the COVID-19 pandemic cannot be fully known. Data collection occurred from March 23-May 3, 2020. Maryland's stay-at-home directive was ordered on Mar. 30, 2020 (Wenger & Wood, 2020), but closures of non-essential business, school closings, and other restrictions began earlier (Dance, 2020).
-
- Watson N F, Badr M S, Belenky G, et al.; Consensus Conference Panel. Joint consensus statement of the American Academy of Sleep Medicine and Sleep Research Society on the recommended amount of sleep for a healthy adult: methodology and discussion. Sleep. 2015 Aug. 1; 38(8):1161-83.
- Liu Y, Wheaton A G, Chapman D P, et al. Prevalence of healthy sleep duration among adults-United States, 2014. MMWR Morb Mortal Wkly Rep. 2016 Feb. 19; 65(6):137-41.
- NHLBI (National Heart, Lung, and Blood Institute). National Sleep Disorders Research Plan, 2003. Bethesda, Md.: National Institutes of Health; 2003.
- Altman, B. R., Mian, M. N., Slavin, M., & Earleywine, M. (2019). Cannabis expectancies for sleep. Journal of Psychoactive Drugs, 51(5), 405-412. https://doi.org/10.1080/02791072.2019.1643053.
- Babson, K. A., Sottile, J., & Morabito, D. (2017). Cannabis, cannabinoids, and sleep: A review of the literature. Current Psychiatry Reports, 19(4), 23. https://doi.org/10.1007/s11920-017-0775-9.
- Barratt, E. S., Beaver, W., & White, R. (1974). The effects of marijuana on human sleep patterns. Biological Psychiatry, 8(1), 47-54.
- Bowles, N. P., Herzig, M. X., & Shea, S. A. (2017). Recent legalization of cannabis use: Effects on sleep, health, and workplace safety. Nature and Science of Sleep, 9, 249-251. https://doi.org/10.2147/NSS.S152231
- Chait, L. D. (1990). Subjective and behavioral effects of marijuana the morning after smoking. Psychopharmacology, 100(3), 328-333. https://doi.org/10.1007/BF02244601
- Cousens, K., & DiMascio, A. (1973). (−)
Delta 9 THC as an hypnotic: An experimental study of three dose levels. Psychopharmacologia, 33(4), 355-364. https://doi.org/10.1007/BF00437513 - Dance, S. (2020, March 24). Even without ‘shelter in place’ order, Maryland faces some of nation's strictest orders to contain coronavirus. The Baltimore Sun. Retrieved from https://www.baltimoresun.com
- Feinberg, I., Jones, R., Walker, J. M., Cavness, C., & March, J. (1975). Effects of high dosage delta-9-tetrahydrocannabinol on sleep patterns in man. Clinical Pharmacology & Therapeutics, 17(4),458-66. https://doi.org/10.1002/cpt1975174458
- Gates, P. J., Albertella, L., & Copeland, J. (2014). The effects of cannabinoid administration on sleep: A systematic review of human studies. Sleep Medicine Reviews, 18, 477-487. https://doi.org/10.1016/j.smrv.2014.02.005
- National Conference of State Legislatures. (2020, March 10). State Medical Marijuana Laws. http://www.ncsl.org/research/health/state-medical-marijuana-laws.aspx
- O'Hare, E., Flanagan, D., Penzel, T., Garcia, C., Frohberg, D., & Heneghan, C. (2014). A comparison of radio-frequency biomotion sensors and actigraphy versus polysomnography for the assessment of sleep in normal subjects. Sleep and Breathing, 19(1), 91-98. https://doi.org/10.1007/s11325-014-0967-z
- Ohayon M. M., Carskadon M. A., Guilleminault, C., & Vitiello M. V. (2004) Meta-analysis of quantitative sleep parameters from childhood to old age in healthy individuals: Developing normative sleep values across the human lifespan. Sleep, 27(7), 1255-1273.
- Ohayon, M., Wickwire, E. M., Hirshkowitz, M., Albert, S. M., Avidan, A., Daly, F. J., et al. (2017). National Sleep Foundation's sleep quality recommendations: First report. Sleep Health, 3(1), 6-19. doi: 10.1016/j.sleh.2016.11.006
- Piper, B. J., DeKeuster, R. M., Beals, M. L., Cobb, C. M., Burchman, C. A., Perkinson, L., Lynn, S. T., Nichols, S. D. & Abess, A. T. (2017). Substitution of medical cannabis for pharmaceutical agents for pain, anxiety, and sleep. Journal of Psychopharmacology, 31(5), 569-575. doi: 10.1177/0269881117699616
- Russo, E. B. (2011). Taming THC: Potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. British Journal of Pharmacology, 163(7), 1344-1364. https://doi.org/10.1111/j.1476-5381.2011.01238.x
- Schade, M. M., Bauer, C. E., Murray, B. R., Gahan, L., Doheny, E. P., Kilroy, H., Zaffaroni, A., & Montgomery-Downs, H. E. (2019). Sleep validity of a non-contact bedside movement and respiration-sensing device. Journal of Clinical Sleep Medicine, 15(7), 1051-61. https://doi.org/10.5664/jcsm.7892
- SleepScore Labs. (2020, April 22). Are We Getting More Sleep During COVID-19 Restrictions? Effects of THC combined with CBN on staying asleep. https://www.sleepscore.com/category/trouble-staying-asleep/?rfr=ssl-top-nav
- SleepScore Labs. (2020, May 15). Effects of THC combined with CBN on staying asleep. https://www.sleepscore.com/category/trouble-staying-asleep/?rfr=ssl-top-nav
- Wenger, Y., & Wood, P. (2020, March 30). Gov. Hogan issues stay-at-home order for Maryland to stop spread of the coronavirus. The Baltimore Sun. Retrieved from https://www.baltimoresun.com
- Yoshida, H., Usami, N., Ohishi, Y., Watanabe, K., Yamamoto, I., & Yoshimura, H. (1995). Synthesis and pharmacological effects in mice of halogenated cannabinol derivatives. Chemical and Pharmaceutical Bulletin, 43(2), 335-337. https://doi.org/10.1248/cpb.43.335
- Zaffaroni, A., Coffey, S., Dodd, S., Kilroy, H., Lyon, G., O'Rourke, D., Lederer, K., Fietze, I., & Penzel, T. (2019). Sleep staging monitoring based on sonar smartphone technology. 41st Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC) (pp. 2230-2233). Berlin: IEEE. doi: 10.1109/EMBC.2019.8857033
- Zaffaroni, A., Doheny, E. P., Gahan, L., Ivanov, Y., Kilroy, H., O' Mahony, N, & O' Rourke, D. (2017). Non-contact estimation of sleep staging. In H. Eskola, O. Väisänen, J. Viik, & J. Hyttinen (Eds.), EMBEC & NBC 2017. EMBEC 2017, NBC 2017. IFMBE Proceedings, 65. Singapore: Springer. https://doi.org/10.1007/978-981-10-5122-7_20
- Unless otherwise required by context herein, singular terms shall include pluralities and plural terms shall include the singular. Singular forms “a”, “an” and “the”, and singular use of any word, include plural referents unless expressly and unequivocally limited on one referent.
- It is understood the use of the alternative (e.g., “or”) herein is taken to mean either one or both or any combination thereof of the alternatives. The term “and/or” used herein is to be taken mean specific disclosure of each of the specified features or components with or without the other. For example, the term “and/or” as used in a phrase such as “A and/or B” herein is intended to include “A and B,” “A or B,” “A” (alone), and “B” (alone). Likewise, the term “and/or” as used in a phrase such as “A, B, and/or C” is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).
- As used herein, terms “comprising”, “including”, “having” and “containing”, and their grammatical variants, as used herein are intended to be non-limiting so that one item or multiple items in a list do not exclude other items that can be substituted or added to the listed items. It is understood that wherever aspects are described herein with the language “comprising,” otherwise analogous aspects described in terms of “consisting of” and/or “consisting essentially of” are also provided.
- As used herein, the term “about” refers to a value or composition that is within an acceptable error range for the particular value or composition as determined by one of ordinary skill in the art, which will depend in part on how the value or composition is measured or determined, i.e., the limitations of the measurement system. For example, “about” or “approximately” can mean within one or more than one standard deviation per the practice in the art. Alternatively, “about” or “approximately” can mean a range of up to 10% (i.e., ±10%) or more depending on the limitations of the measurement system. For example, about 5 mg can include any number between 4.5 mg and 5.5 mg. When particular values or compositions are provided in the instant disclosure, unless otherwise stated, the meaning of “about” or “approximately” should be assumed to be within an acceptable error range for that particular value or composition.
- The term “administering”, “administered” and grammatical variants refers to the physical introduction of an agent to a subject, using any of the various methods and delivery systems known to those skilled in the art. Exemplary routes of administration include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral routes of administration, for example by injection or infusion. The phrase “parenteral administration” means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion, as well as in vivo electroporation. Non-parenteral routes include oral, topical, epidermal or mucosal route of administration, for example, intranasally, vaginally, rectally, sublingually or topically. Administering can also be performed, for example, once, a plurality of times, and/or over one or more extended periods.
- Throughout this application various publications, patents, and/or patent applications are referenced. The disclosures of the publications, patents and/or patent applications are hereby incorporated by reference in their entireties into this application in order to more fully describe the state of the art to which this disclosure pertains.
- The above disclosure contains various examples of oral pulse-release compositions and dosage forms, and methods of treating sleep disorders in a subject by administering the oral pulse-release compositions and dosage forms. Aspects of these various examples may all be combined with one another, even if not expressly combined in the present disclosure, unless they are clearly mutually exclusive.
- The above disclosed subject matter is to be considered illustrative, and not restrictive, and the appended claims are intended to cover all such modifications, enhancements, and other implementations which fall within the true spirit and scope of the present disclosure. Thus, to the maximum extent allowed by law, the scope of the present disclosure is to be determined by the broadest permissible interpretation of the following claims and their equivalents and shall not be restricted or limited by the foregoing detailed description.
Claims (41)
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US18/297,973 US11779563B2 (en) | 2021-01-29 | 2023-04-10 | Oral cannabinoid pharmaceutical compositions and methods of treating sleep disorders |
US18/455,378 US20230404966A1 (en) | 2021-01-29 | 2023-08-24 | Oral cannabinoid pharmaceutical compositions and methods of treating sleep disorders |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US202163143320P | 2021-01-29 | 2021-01-29 | |
US17/586,119 US11654130B2 (en) | 2021-01-29 | 2022-01-27 | Oral cannabinoid pharmaceutical compositions and methods of treating sleep disorders |
US18/297,973 US11779563B2 (en) | 2021-01-29 | 2023-04-10 | Oral cannabinoid pharmaceutical compositions and methods of treating sleep disorders |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US17/586,119 Division US11654130B2 (en) | 2021-01-29 | 2022-01-27 | Oral cannabinoid pharmaceutical compositions and methods of treating sleep disorders |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US18/455,378 Continuation US20230404966A1 (en) | 2021-01-29 | 2023-08-24 | Oral cannabinoid pharmaceutical compositions and methods of treating sleep disorders |
Publications (2)
Publication Number | Publication Date |
---|---|
US20230248693A1 true US20230248693A1 (en) | 2023-08-10 |
US11779563B2 US11779563B2 (en) | 2023-10-10 |
Family
ID=80786745
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US17/586,119 Active US11654130B2 (en) | 2021-01-29 | 2022-01-27 | Oral cannabinoid pharmaceutical compositions and methods of treating sleep disorders |
US18/297,973 Active US11779563B2 (en) | 2021-01-29 | 2023-04-10 | Oral cannabinoid pharmaceutical compositions and methods of treating sleep disorders |
US18/455,378 Pending US20230404966A1 (en) | 2021-01-29 | 2023-08-24 | Oral cannabinoid pharmaceutical compositions and methods of treating sleep disorders |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US17/586,119 Active US11654130B2 (en) | 2021-01-29 | 2022-01-27 | Oral cannabinoid pharmaceutical compositions and methods of treating sleep disorders |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US18/455,378 Pending US20230404966A1 (en) | 2021-01-29 | 2023-08-24 | Oral cannabinoid pharmaceutical compositions and methods of treating sleep disorders |
Country Status (4)
Country | Link |
---|---|
US (3) | US11654130B2 (en) |
EP (1) | EP4284345A1 (en) |
CA (1) | CA3198142A1 (en) |
WO (1) | WO2022165009A1 (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP4284345A1 (en) * | 2021-01-29 | 2023-12-06 | Curio IP, LLC | Oral cannabinoid pharmaceutical compositions and methods of treating sleep disorders |
US20230338399A1 (en) * | 2022-04-22 | 2023-10-26 | Curio Ip, Llc | Oral cannabinoid pharmaceutical compositions and methods of treating inflammatory gastrointestinal disorders |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11654130B2 (en) * | 2021-01-29 | 2023-05-23 | Curio Ip, Llc | Oral cannabinoid pharmaceutical compositions and methods of treating sleep disorders |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011063164A2 (en) | 2009-11-18 | 2011-05-26 | Steady Sleep Rx Co., Inc. | Sustained release cannabinoid medicaments |
WO2015025312A1 (en) * | 2013-08-21 | 2015-02-26 | Cannabics Pharmaceuticals Inc | Compositions for combined immediate and sustained release of cannabinoids, methods of manufacture and use thereof |
US10772837B2 (en) | 2017-03-16 | 2020-09-15 | CannTab Therapeutics, Ltd | Modified release multi-layer tablet cannabinoid formulations |
CA3076929A1 (en) | 2017-09-25 | 2019-03-28 | Canopy Health Innovations | Compositions comprising cannabidiol, tetrahydrocannabinol, terpenes, and flavonoids and use thereof in the treatment of insomnia |
US11504350B2 (en) | 2017-10-25 | 2022-11-22 | Day Three Labs Manufacturing Inc. | Cannabinoid compositions and methods of use thereof |
WO2019082171A1 (en) | 2017-10-27 | 2019-05-02 | Alvit Pharma | Oral cannabinoid compositions with improved bioavailability |
-
2022
- 2022-01-27 EP EP22704658.8A patent/EP4284345A1/en active Pending
- 2022-01-27 WO PCT/US2022/014063 patent/WO2022165009A1/en active Application Filing
- 2022-01-27 CA CA3198142A patent/CA3198142A1/en active Pending
- 2022-01-27 US US17/586,119 patent/US11654130B2/en active Active
-
2023
- 2023-04-10 US US18/297,973 patent/US11779563B2/en active Active
- 2023-08-24 US US18/455,378 patent/US20230404966A1/en active Pending
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11654130B2 (en) * | 2021-01-29 | 2023-05-23 | Curio Ip, Llc | Oral cannabinoid pharmaceutical compositions and methods of treating sleep disorders |
Also Published As
Publication number | Publication date |
---|---|
WO2022165009A1 (en) | 2022-08-04 |
US11779563B2 (en) | 2023-10-10 |
CA3198142A1 (en) | 2022-08-04 |
US20230404966A1 (en) | 2023-12-21 |
US20220249429A1 (en) | 2022-08-11 |
US11654130B2 (en) | 2023-05-23 |
EP4284345A1 (en) | 2023-12-06 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11779563B2 (en) | Oral cannabinoid pharmaceutical compositions and methods of treating sleep disorders | |
US10702529B2 (en) | Compositions and methods for treating insomnia | |
ES2706407T3 (en) | Immediate-release pharmaceutical compositions comprising oxycodone and naloxone | |
JP2022066315A (en) | Methods and compositions for treatment of attention deficit disorder | |
AU2013344281B2 (en) | Pharmaceutical compositions comprising hydromorphone and naloxone | |
JP6228212B2 (en) | Nootropic composition for improving memory ability | |
US20220331305A1 (en) | Pharmaceutical Compositions Comprising Alpelisib | |
JP2015522612A (en) | Nicotinamide derivatives in the treatment of acute coronary syndrome | |
US10849856B2 (en) | Melatonin mini-tablets and method of manufacturing the same | |
JP6738797B2 (en) | Ret syndrome drug | |
US20130078287A1 (en) | Pharmaceutical compositions of ibuprofen and an h2 receptor antagonist | |
Borgen et al. | The effect of omeprazole on the bioavailability of sodium oxybate | |
Patat et al. | Safety, pharmacokinetics (PK) and pharmacodynamics (PD) of ascending multiple doses of SRA‐333 in healthy subjects | |
Preston et al. | Differential effects of methadone dose/contingency management combinations on abstinence from heroin and cocaine | |
Mamatha | Preparation and characterization of diltiazem hydrochloride tablets for controlled release |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: CURIO IP, LLC, MARYLAND Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:RUDNIC, EDWARD M.;BRONFEIN, MICHAEL;SIGNING DATES FROM 20220127 TO 20220131;REEL/FRAME:063276/0018 |
|
FEPP | Fee payment procedure |
Free format text: ENTITY STATUS SET TO UNDISCOUNTED (ORIGINAL EVENT CODE: BIG.); ENTITY STATUS OF PATENT OWNER: SMALL ENTITY |
|
FEPP | Fee payment procedure |
Free format text: ENTITY STATUS SET TO SMALL (ORIGINAL EVENT CODE: SMAL); ENTITY STATUS OF PATENT OWNER: SMALL ENTITY |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: NOTICE OF ALLOWANCE MAILED -- APPLICATION RECEIVED IN OFFICE OF PUBLICATIONS |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: PUBLICATIONS -- ISSUE FEE PAYMENT RECEIVED |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: PUBLICATIONS -- ISSUE FEE PAYMENT VERIFIED |
|
STCF | Information on status: patent grant |
Free format text: PATENTED CASE |